How I Healed my Cancer

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself!

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Estrogen and Human Breast Cancer

Breast Cancer Research Laboratory, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA E-mail J_Russo fccc.edu Breast cancer is the most common neoplastic disease in women worldwide. Development of breast cancer is profoundly influenced by prolonged exposure to estrogens, but the role of estrogen in the development of human breast cancer has remained elusive. There is evidence that in situ metabolism of estrogens by estrone sulfatase and aromatase results in a high level of active estrogens in the breast. Two mechanisms have been considered to be responsible for the potential carcinogenicity of estrogens receptor-mediated hormonal activity and cytochrome P450-mediated metabolic activation. The receptor-mediated hormonal activity of estrogen has generally been related to stimulation of cellular proliferation, resulting in more opportunities for accumulation of genetic damages leading to carcinogenesis. Since local synthesis of estrogen in the stromal component...

Some General Remarks About Cancer And Cancer Chemotherapy

Cancer is a collective term used for a group of diseases that are characterized by the loss of control of the growth, division, and spread of a group of cells, leading to a primary tumor that invades and destroys adjacent tissues. It may also spread to other regions of the body through a process known as metastasis, which is the cause of 90 of cancer deaths. Cancer remains one of the most difficult diseases to treat and is responsible for about 13 of all deaths worldwide, and this incidence is increasing due to the ageing of population in most countries, but specially in the developed ones. Cancer is normally caused by abnormalities of the genetic material of the affected cells. Tumorigenesis is a multistep process that involves the accumulation of successive mutations in oncogenes and suppressor genes that deregulates the cell cycle. Tumorigenic events include small-scale changes in DNA sequences, such as point mutations larger-scale chromosomal aberrations, such as translocations,...

Human Cancers

10.1 Common properties of hematological 12 Cancers of the 12.1 Carcinogenesis in the 13 Colon 13. 1 Natural history of colorectal 13.3 Progression of Colon Cancer and the Multi-Step Model 13.6 Inflammation and colon Box 13.1 Positional cloning of tumor suppressor genes in hereditary cancers .288 14 Bladder 14.1 Histology and etiology of bladder 14.2 Molecular alterations in invasive bladder 14.3 Molecular alterations in papillary bladder 14.4 A comparison of bladder cancer Box 14.1 Tumor suppressor candidates at 9q in bladder cancer 306 15.1 The diversity of renal 15.3 Molecular biology of inherited kidney 16 Liver 16.1 Etiology of liver 17 Stomach 17.1 Etiology of stomach 17.2 Molecular mechanisms in gastric 17.3 Helicobacter pylori and stomach Box 17.1 Barrett esophagus and esophageal 18 Breast 18.2 Etiology of breast 18.3 Hereditary breast 18.4 Estrogen receptors andERBBproteins in breast cancer 373 18.5 Classification of breast 19 Prostate 19.1 Epidemiology of prostate 19.2...

Natural Products In Cancer Chemotherapy

Plants, micoorganisms, and, more recently, marine organisms of various types have traditionally represented a main source of cytotoxic anticancer agents since the beginning of chemotherapy.21 Even if the new technologies of combinatorial chemistry and high-throughput screening (HTS) represent an important step in drug discovery, the role of natural sources in providing new cytotoxics should not be disregarded for the future.22 The number of microbial species studied in this regard is still very low, and the marine ecosystem is largely unexplored. Around half of the drugs currently in clinical use as anticancer drugs are of natural product origin, and it has been estimated that about 60 of new chemical entities (NCEs) introduced in the 1981-2002 period in this field were natural products or were derived from a natural lead compound.23 Despite this statistic, pharmaceutical companies have neglected in the recent past the development of potential natural drug candidates in favor of...

Microarrays For Cancer Research Historical Perspectives

Gene expression profiling in cancer has become routine in recent years and to date encompasses the largest category of research using DNA microarrays. Microarray analysis has been used to assess transcriptome-level (expression analysis) (1) and genome-level (single-nucleotide polymorphism (2), amplification deletion (3)) differences in cancerous versus normal cell samples. Furthermore, microarray analysis has been used to identify putative diagnostic and prognostic markers that will hopefully translate into clinical tests that can be used to stratify patients and determine treatment regimens (4). Comparison of treatment response at both the RNA and DNA levels has been conducted in an effort to further direct the most optimal therapy for an individual patient. Classically, many large-scale studies have revealed groups of genes differentially expressed between cancerous and normal cells, including genes known to be important for neoplastic transformation. However, despite the vast...

Brief Comment About Cancer Nanotechnology

Nanotechnology is a field of applied science that covers a broad range of topics in which matter is controlled on a scale of 1-1,000 nm. Its application to cancer chemotherapy includes the use of nanovectors for the targeted delivery of antitumor compounds and imaging contrast agents, aiming at increasing the efficacy per dose of therapeutic or imaging contrast formulations.28 Liposomes, which are the simplest forms of nanovectors, use the EPR effect to increase drug concentration at tumor sites, and were first applied to anthracy-clines in order to avoid their cardiotoxicity. The refinement of liposomes and their application in cancer chemotherapy is still an active field of research, although other novel drug delivery modalities have appeared.29,30 In general, a nanovector has a core constituent material, a therapeutic and or imaging payload, and biological surface modifiers to enhance biodistribution and tumor targeting. Among several types of nanoparticles directed to enhance the...

Stem Cell Theory Of Cancer

While natural heterogeneity of cancer specimens is well documented, and the ability to isolate hundreds to thousands of cells with techniques such as LCM have allowed microarray analysis of more pure populations, the recent re-introduction of the cancer stem cell theory (24,25) has presented an extreme example of the need to isolate rare populations of cells. Cancer stem cells appear to exist at a frequency on the order of 1 in 1000 cells (26). While obtaining completely pure populations of stem cells remains difficult, highly enriched populations of these cells can be isolated using flow cytometry separating on the basis of the presence of certain specific cell markers. One hypothesis is that cancer stem cells are relatively immune to current therapeutic methodologies, due in large part to the fact that these cells divide only infrequently and are generally quiescent. As these cells also have the potential to cause the formation of a new cancer, therapeutics targeted to these...

Implications of Estrogens in Human Breast Carcinogenesis

Although 67 of breast cancers are manifested during the postmenopausal period, a vast majority, 95 , are initially hormone-dependent 14 . This indicates that estrogens play a crucial role in their development and evolution. It has been established that in situ metabolism of estrogens through aromatase-mediated pathway is correlated with the risk of developing breast cancer 66-69 . A recent finding that expression of estrone sulfatase is inversely correlated with re lapse-free survival of human breast cancer patients 78 reiterates the importance of estrone sulfatase-mediated local production of estrogen in the development and progression of human breast cancer. However, it is still unclear whether estrogens are carcinogenic to the human breast. Most of the current understanding of carcinogenicity of estrogens is based on studies in experimental animal systems and clinical observations of a greater risk of endome-trial hyperplasia and neoplasia associated with estrogen supplementation...

An Overview Of The Cancer Problem

What is commonly called 'human cancer' comprises in fact more than 200 different diseases. Together, they account for about one fifth of all deaths in the industrialized countries of the Western World. Likewise, one person out of three will be treated for a severe cancer in their life-time. In a typical Western industrialized country like Germany with its 82 million inhabitants, > 400,000 persons are newly diagnosed with cancer each year, and 200,000 succumb to the disease. Since the incidence of most cancers increases with age, these figures are going to rise, if life expectancy continues to increase. If one considers the incidence and mortality by organ site, while ignoring further biological and clinical differences, cancers fall into three large groups (Figure 1.1). Cancers arising from epithelia are called 'carcinomas'. These are the most prevalent cancers overall. Four carcinomas are particular important with regard to incidence as well as mortality. Cancers of the lung and...

Does PET Hypoxia Imaging Detect Hypoxia and Regions of Radiation Resistance in Human Cancers

With regard to the correlation between hypoxia PET imaging tracers and other approaches for hypoxia assessment, such as the expression of intrinsic tissue hypoxia markers (i.e., tumor expression of hypoxia-regulated proteins or genes), the published data for human tumors are even more meager Grigsby et al. 23 compared 64Cu-ATSM-PET to several hypoxia-related biomarkers, including vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX2), epithelial growth factor receptor (EGFR), carbonic anhydrase IX (CAIX), and the apoptotic index in 15 patients with cervical cancer. They found that the only significant correlation was with tumoral CAIX and the apoptosis level, at P < 0.05. Hu et al. 24 reported that the maximum intratumoral standardized uptake value (SUVmax) of pretreatment 18FETNIM in 19 patients with non-small cell lung cancer (NSCLC) Regardless of the correlation between PET-based hypoxia imaging and other approaches for hypoxia detection, the most important question...

Characteristic Properties Of Cancers And Cancer Cells

In spite of their diversity, human cancers share several fundamental properties (Table 1.3). Different cancers display each of these to different extents. Moreover, these properties may be acquired step by step and become evident at various stages during the progression of a cancer. Most of these properties individually are also found in other diseases and some are even exhibited during physiological adaptive responses. However, the combination of uncontrolled cell proliferation, altered differentiation and metabolism, genomic instability, and invasiveness with eventual metastasis is unique to and defines cancer. Increased and autonomous cell proliferation The most obvious property of tumors is growth beyond normal measures. In fact, the term 'tumor' when used in a broader sense designates every abnormally large structure in the human body, also including swellings or fluid-filled cysts. More precisely, then, cancers belong to those tumors caused primarily by increased cell...

Grading And Staging Of Cancer

Physicians use a system called staging to describe the size of a tumor and whether it has spread beyond the area in which it started. Each type of cancer has a different system of staging that helps to describe the progress of that cancer. In general, there are a number of stages that begin with a small, localized cancer, right through to one that has spread extensively into surrounding areas of the body, a so-called advanced cancer. Knowing the stage is important in deciding on the most appropriate treatment. After the determination is made as to the type of cancer, the cancer is graded a measurement of the aggressiveness of the tumor. Most cancer cells are graded by how much they look like normal cells. Grading is done in the lab using cancerous cells taken during biopsy. There are many different types of grading systems used by doctors. These vary depending on the cancer. In general, however, lower grades mean a less aggressive behavior, and higher grades predict for a relatively...

The Role of Sex Hormones in Prostate Cancer

Prostate cancer is the most frequently diagnosed malignancy and second leading cause of cancer death in men in Western countries. Little is understood about its causes, but steroid hormones, particularly androgens, are suspected to play a major role. Human populations at high risk for prostate cancer may have slightly higher androgen production, circulating androgens, 5a-reductase activity, or androgen receptor transactivation activity than low-risk populations. Elevated circulating estrogens have been found in some high risk populations, such as African American men, suggesting estrogen involvement. Studies in rats have clearly demonstrated that testosterone is a weak complete carcinogen and a strong tumor promotor for the prostate, but the exact mechanisms of these activities are not clear. Treatment of rats with a combination of testosterone and 17 -estradiol can induce prostate cancer at high incidence, while androgens alone cause a low prostate cancer incidence, indicating...

Age at Diagnosis for Some Common Cancers and Some Cancers That Are More Common amongYounger Individualsa

Cancer Source Ries, L. et al., SEER Cancer Statistics Review, 1973-Bethesda, MD, 2002. 1999, National Cancer Institute, were 65 years of age or older. The most common prevalent cancer sites are the breast, prostate, and colon rectum. Figure 1.6 shows the distribution of cancer diagnoses for cancer survivors in 1999. The three common sites mentioned above account for slightly more than 50 of the cancers among survivors. One notes that although lung cancer is the second most common type of cancer among men and women, only 4 of the current survivors have this type of cancer. FlGURE 1.6 Most common types of prevalent cancer in the U.S.

Increased Incidence of Testicular and Prostate Cancer

The incidence of testicular cancer has increased quite dramatically in many countries with cancer registries, including Scandinavia, the countries around the Baltic Sea, Germany, the UK, the USA and New Zealand.3 34 it is interesting that although the incidences of testicular cancer in Denmark and Finland are rising, rates in Finland are several times lower than in Denmark further study of this apparent geographical gradient may give important clues on aetiology. The incidence of prostate cancer also appears to have risen in many countries 536

The Epidemiology of Prostate Cancer

Prostate cancer incidence and mortality rates have increased in the US over the few decades preceding the frequent use of prostate specific antigen (PSA) for early detection 10 . Incidence rates have increased substantially since the mid-1980s because of use of PSA screening for early detection 1 ,but rates have recently begun to decline 11 . In 1999,179,300 new cases of prostate cancer are expected and 37,000 deaths from this malignancy 12 . The epidemiology of prostatic cancer has been reviewed in depth elsewhere 10,13-17 . The most important potential risk factors are summarized below, with special attention to those possibly related to hormonal factors.

Reduces the risk of colorectal cancer

Colorectal cancer, which is characterized by neoplasia in the colon, rectum, or vermiform appendix, is the third most commonly diagnosed cancer in the world. More than half of the deaths of colorectal cancer are reported from the developed regions of the world. Several studies suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer (Chao et al., 2005 Wakai et al., 2007). Dietary fiber has been hypothesized to involve in reducing the risk of colorectal cancer through several protective mechanisms including dilution of fecal carcinogens, reduction of transit time of feces through the bowel, production of short chain fatty acids which promote anticarcinogenic action, and binding of carcinogenic bile acids (Lipkin et al, 1999). Soluble fiber in seaweed can bind with water 20 times of their own volume exhibiting strong hydrocolloidal properties of its network structure. Therefore, seaweed added to the...

Cancer As A Genetic Disease

The characteristic properties of cancer cells ( 1.3) are to a large extent the consequences of genetic changes in the tumor cells. Indeed, genomic instability is one of the properties defining cancer and the aberrant structure of the nucleus seen in many cancer cells is an obvious morphological consequence of their altered genome. It is plausible that every cancer cell contains structural or numerical alterations of its genome. The number of alterations is not precisely known, and certainly varies with cancer type and stage of progression. Systematic DNA sequencing has yielded estimates of hundreds to thousands of point mutations in some tumors. Screening by arbitrary PCR has suggested an even higher number of alterations for some cancers. Certainly, 20 or more chromosomal aberrations detectable by cytogenetic techniques are not unusual in an advanced carcinoma. It is therefore very appropriate to regard cancer as a genetic disease. Still, a few points must be kept in mind (1) Only a...

Inherited Predisposition To Cancer

Although most genetic alterations in tumor cells develop during the life-time of a patient, the predisposition to cancers can be inherited. Three different types of inheritance can be distinguished. In some families cancers are very frequent and occur (essentially) in each generation. This is a general hallmark of autosomal-dominant inherited diseases with high penetrance. The families may be plagued by specific cancers, rarer ones such as retinoblastoma, or common cancers such as breast cancer, or by various types of cancer, such as in Li-Fraumeni-syndrome (Table 2.2). Typically, cancers manifest at a lower than average age of onset and also unusually often at multiple sites or bilaterally in paired organs, such as the eyes, kidney and breast. These are two further criteria pointing to inherited cancers. In some cases, cancer predisposition is associated with developmental defects, e.g. in the Gorlin and Cowden syndromes. This is a fourth, although not as strict criterion. The...

Challenge of Studying Anticancer Agents

There are a number of limitations specific to the study of the pharmacogenetics of anticancer agents. Anticancer agents affect tumor and non-tumor cells. They have a narrow therapeutic index and a wide toxicity profile with the extreme end of the spectrum resulting in death. Thus, it is particularly important to identify genetic polymorphisms associated with toxicities related to these medications. Identifying heritable polymorphisms associated with chemotherapy cannot be performed in related, healthy individuals, thus forcing researchers to consider alternatives to current approaches.

Increased Incidence of Female Breast Cancer

In women, the incidence of breast cancer has increased steadily over the past few decades in a number of countries including Finland, Denmark, USA and the UK.3i.39.4o in Finland, for example, the incidence rose from 25 per 100000 in 1953 to more than 40 per 100 000 in 1980. Although improved detection may be partly responsible, the underlying upward trend is estimated as about 1 per year since 1940. A number of factors that increase breast cancer risk have been identified, including diet, calorie intake and alcohol consumption, but lifetime exposure to oestrogens (age at menarche and menopause, use of contraceptive pill, etc.) is of major importance and environmental oestrogens might contribute to overall exposure and thereby to the rising incidence of the disease.

Advantages and Limitations of LCLs for Evaluating the Pharmacogenomics ofAnticancer Agents

The greatest advantages of the use of CEPH cell lines for studying human variation in response to drugs is that they provide a system to perform phenotypic studies of anticancer agents that would be considered unsafe and unethical in healthy volunteers. The confounders of in vivo studies (metabolism, pharmacokinetics, clearance) are ignored, which can be considered both an advantage and disadvantage. CEPH cells can be grown under identical conditions thus the phenotype to be tested is in a well-controlled, isolated system without the confounders present in vivo.

Steroid Hormonal Factors in Populations with Different Risk for Prostate Cancer

Ahluwalia et al. 139 studied African Americans and black Nigerian men that were matched controls in a case control study of prostate cancer. Plasma levels of testosterone and estrone were significantly higher in the Americans than in the Nigerian men, whereas levels of DHT and 17 -estradiol were not different. Similar differences were found for the prostate cancer cases. Hill et al. 62-64 compared the hormonal status of small groups of middle-aged African American, European American, and black (rural) South African men consuming their customary diets. In a separate study, African American, European American, and black South African boys and young African American and Ross et al. 133 compared healthy young African-American men and young US Caucasian males. Total circulating testosterone and free testosterone were 20 higher in the black men than in the white group. Serum estrone concentrations were also higher (by 16 ) in the blacks than in the whites. There were no differences between...

Studies Of Cancer In Humans

Three types of epidemiological studies of cancer contribute to the assessment of carcinogenicity in humans cohort studies, case-control studies and correlation (or ecological) studies. Rarely, results from randomized trials may be available. Case series and case reports of cancer in humans may also be reviewed. Cohort and case-control studies relate the exposures under study to the occurrence of cancer in individuals and provide an estimate of relative risk (ratio of incidence or mortality in those exposed to incidence or mortality in those not exposed) as the main measure of association. In correlation studies, the units of investigation are usually whole populations (e.g. in particular geographical areas or at particular times), and cancer frequency is related to a summary measure of the exposure of the population to the agent, mixture or exposure circumstance under study. Because individual exposure is not documented, however, a causal relationship is less easy to infer from...

Measures of Anticancer Agent Response

Until recently, CEPH LCLs have represented an untapped resource for identifying heritable traits related to anticancer drug sensitivity. Cytotoxicity can be measured as cell growth inhibition using a short-term assay using a colorimetric such as alamarBlue, propidium iodide or MTT, to name a few (Fig. 1) (17,18,19). These assays focus on the ability of mitochondrial reduction of dye, rather than a direct measure of cytotoxicity. However, the dye-reduction approaches are very amenable to high-throughput assays. In addition, apoptosis can be measured using ELISA, flow cytometry, or similar approaches. Other phenotypes might include phosphorylation of enzymes, transport of known substrates, expression levels of genes, enzyme activity, protein levels or drug-induced DNA breaks (13,14,17,19,20,21).

Studies Of Cancer In Experimental Animals

All known human carcinogens that have been studied adequately in experimental animals have produced positive results in one or more animal species (Wilbourn et al., 1986 Tomatis et al., 1989). For several agents (aflatoxins, 4-aminobiphenyl, azathio-prine, betel quid with tobacco, bischloromethyl ether and chloromethyl methyl ether (technical grade), chlorambucil, chlornaphazine, ciclosporin, coal-tar pitches, coal-tars, combined oral contraceptives, cyclophosphamide, diethylstilboestrol, melphalan, 8-methoxypsoralen plus ultraviolet A radiation, mustard gas, myleran, 2-naphthylamine, nonsteroidal estrogens, estrogen replacement therapy steroidal estrogens, solar radiation, thiotepa and vinyl chloride), carcinogenicity in experimental animals was established or highly suspected before epidemiological studies confirmed their carcinogenicity in humans (Vainio et al., 1995). Although this association cannot establish that all agents and mixtures that cause cancer in experimental animals...

Other Data Relevant To An Evaluation Of Carcinogenicity And Its Mechanisms

In coming to an overall evaluation of carcinogenicity in humans (see pp. 25-27), the Working Group also considers related data. The nature of the information selected for the summary depends on the agent being considered. Concise information is given on absorption, distribution (including placental transfer) and excretion in both humans and experimental animals. Kinetic factors that may affect the dose-response relationship, such as saturation of uptake, protein binding, metabolic activation, detoxification and DNA repair processes, are mentioned. Studies that indicate the metabolic fate of the agent in humans and in experimental animals are summarized briefly, and comparisons of data on humans and on animals are made when possible. Comparative information on the relationship between exposure and the dose that reaches the target site may be of particular importance for extrapolation between species. Data are given on acute and chronic toxic effects (other than cancer), such as Tests...

Epidemiology The Case For Metals And Cancer

Numerous epidemiological studies have examined the effects of metals on human cancer. The first epidemiological studies linking metals and human cancer date from the early 1900s.7 Based on available epidemiological data, a number of government agencies including the U.S. Environmental Protection Agency, the Occupational Safety and Health Administration, the National Institute for Occupational Safety and Health, and the National Toxicology Program, as well as nongovernmental advisory organizations such as the American Conference of Governmental Industrial Hygienists and the International Agency for Research on Cancer have classified metals with regard to their carcinogenicity in humans. Although there is some disagreement among these organizations as to the carcinogenic potential of specific metal compounds, there is general agreement among them that a given metal (chromium, for example) may occur in carcinogenic forms. Table 3.1 lists the metals and metalloids that have been...

Hormonal Induction of Prostate Cancer in Laboratory Animals

With the exception of dogs and humans, spontaneously occurring prostate cancer is rare in most species 5-7,190 . It not understood why prostate cancer is so common in men whereas it is very rare in almost all other species. As indicated earlier, there are compelling reasons to implicate hormones, particularly androgenic and estrogenic steroids, in human prostate carcinogenesis. As will be demonstrated in the following sections, the same steroid hormones are also very powerful factors in the induction of prostate cancer in rodent species in which spontaneous prostate cancer is rare 17,56,191 . However, it is important first to point out that the various lobes of the rat prostate differ in their propensity to develop prostate carcinomas, either spontaneously or induced by carcinogens or hormones 17,190,191 . The rodent prostate, unlike the human or canine prostate, consists of distinct paired lobes - the ventral, dorsal, lateral, and anterior lobes the dorsal and lateral lobes are often...

Estrogens And Their Involvement In Carcinogenesis

The natural estrogens induce tumors in a variety of organs in laboratory animals, and high estrogen levels increase the risk of breast and uterine cancer.1 Several mechanisms have been proposed that explain the development of estrogen-dependent tumors. In the first place, the transcription process initiated by the binding of estrogens to their receptors ultimately induces cell proliferation in some target tissues. Examples are breast tissue, where estrogens trigger the proliferation of cells lining the milk glands, thereby preparing the breast to produce milk in case of pregnancy, and the endometrium of the uterus, where they stimulate cell proliferation in order to prepare the uterus for implantation. This proliferative action is one of the physiological roles of estrogens, but it can also lead to the development of breast or uterine cancer because if cells from these tissues already possess a DNA mutation that increases the risk of developing cancer, they will proliferate (along...

FGF19 as a Target for Colorectal Cancer Treatment

FGF19 normally regulates bile acid homeostasis and gall bladder filling (110) however, therapeutic inactivation of FGF19 could be beneficial for the treatment of colon and liver cancer. FGF19 and its cognate receptor FGFR4 were found to be coexpressed in primary human liver, lung, and colon tumors (111). Desnoyers et al. related in vitro binding, phosphorylation, and cell migration of an anti-FGF19 Ab to inhibition of colon cancer xenografts in vivo (111). This Ab abolished FGF19-mediated activity in vitro, inhibited growth of colon tumor xenografts in vivo, and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice (111).

Overview of Experimental Procedure 311 Proteomic Analysis of Cancer Tissues

To analyze the differences of protein expression profiles between cancer tissues and corresponding non-cancerous tissues, the proteomic differential display method was used. In this method, 2-DE and MS were used to identify the proteins. We first separated proteins from cancer tissues and corresponding non-cancerous tissues by 2-DE. Then the protein spots of the samples from cancer tissues were compared to the spots of the samples from corresponding non-cancerous tissues by using software for proteomic differential display. Particular protein spots for which expression was different between cancerous and non-cancerous tissues were cut out from the gels, and were identified by means of MS. Figure 1 shows a workflow of these methods. The proteomic differential display method is a common method to analyze the profiling of protein expression. Usually 2-DE and MS have been used. To detect auto-antibodies expected as cancer biomarkers for HCC, we analyzed serum auto-antibodies...

Testosterone as Tumor Promotor of Prostate Carcinogenesis

Long-term administration of testosterone to rats markedly enhances prostatic carcinogenesis following initial treatment with chemical carcinogens that target the prostate because of tissue-specific metabolism (DMAB and BOP) and or concurrent hormonal stimulation of prostatic cell proliferation 69,70,191,196 -200,202,203,226 . The presence and magnitude of this enhancement appears to depend on several factors 190,191,197 . For example, after a single inj ection of BOP or MNU given to F344 rats without concurrent stimulation of prostatic cell proliferation, long-term testosterone treatment did not enhance prostatic carcinogenesis 200 . High incidences (66-83 ) of adenocarcinomas of the dorsolateral and or anterior prostate were induced by chronic treatment with testosterone following a single administration of MNU or BOP given during stimulation of prostatic cell proliferation in Wistar rats, or during and after ten repeated biweekly injections of DMAB in F344 rats 69,...

Effects of Androgens on Prostate Cancer Induction by Cadmium and Ionizing Radiation

Cadmium can be carcinogenic for the rat ventral prostate as demonstrated by Waalkes and co-workers 227, 228 . The selective sensitivity of the ventral prostate lobe for the carcinogenic action of cadmium is most likely due to the lack of cadmium-binding proteins in this lobe 229 . A single injection of cadmium chloride produced early stage carcinomas in the ventral lobe, but only when cadmium-induced testicular toxicity was avoided, either by keeping the cadmium dose low or by antagonizing the testicular toxicity of cadmium by simultaneous administration of zinc. These observations indicate that cadmium induces proliferative lesions in the rat ventral prostate only when testicular function, conceivably testosterone production, is intact. In addition, these data suggest that androgens also act as tumor promotors in this system, but this hypothesis has not been tested. Other mechanisms may also be involved, because, for example, testosterone considerably increases disposition and...

Defects In Dna Repair And Cancer Susceptibility

It is clear from the previous sections that inherited defects in DNA repair are an important source of susceptibility to cancer. A number of syndromes related to DNA repair carry an increased risk of cancers (Table 3.2). Homozygous mutations in the ATM, NBS1, WRN, FANC, and XP ERCC genes underlie recessively inherited diseases, which confer an increased risk for cancers in the context of syndrome with a wider range of afflictions. Heterozygous mutations in MMR genes and in the BRCAs and perhaps certain ATM mutations lead to cancer predisposition in a dominantly inherited fashion. As a rule, no other consistent symptoms are associated with these mutations. With either type of predisposition, cancers develop at an increased rate as a consequence of an enhanced rate of mutations, either point mutations in MMR deficiency and XP, or chromosomal aberrations in the others. Also typically, in these diseases, cancers appear at an unusually early age. Obviously, the question arises to what...

Proteomics for Pancreatic Cancer Tissues from Patients

Table 3 shows the proteins up-regulated or down-regulated in pancreatic cancer tissues. Shen et al. reported that, in pancreatic cancer tissues, expressions of Mn-SOD, S100A8, annexin A4, cathepsin D, 14-3-3 zeta, tropomyosin 2, actin, ferritin light chain, alpha-enolase, galectin-1, and cyclophilin A increased, and that those of peroxiredoxin Increased or Decreased Proteins in Pancreatic Cancer Tissues from Patients II, DJ-1, HSC 54, carboxypeptidase A1, carboxypeptidase A2, and neuropolypeptide h3 decreased (36). Table 3 shows the summary of the proteins whose expression was different between pancreatic cancer tissues and non-cancerous tissues.

Mechanisms of Hormonal Prostate Carcinogenesis

As stipulated earlier, there are compelling reasons to assume that androgens play a critical role in prostate carcinogenesis, and there is experimental evidence to suggest that estrogens are involved as well 55 . Because of the hormonal nature of these steroids, receptor mediation has been proposed as the major mechanism by which androgens and estrogens act in the causation of prostate cancer 235 . For estrogens, however, non-receptor-mediated genotoxic effects are conceivable, in addition to receptor-mediated processes 55 . For an-drogens, mechanisms other than those mediated by androgen receptors seem unlikely, except for the generation of estrogens via aromatization. These potential mechanisms are discussed in the following sections. Prostatic mesenchyme is known to be a mediator of androgen action in the developing and adult rodent prostate and possibly the human prostate 236, 237 . Therefore, interactions between epithelial and stromal cells in the normal prostate are undoubtedly...

Proteomics for Autoantibodies in Serum from Cancer Patients

Fujita et al. identified auto-antibodies reacting to peroxiredoxin VI in the sera of esophageal cancer patients (37). Hong et al. identified auto-antibodies reacting to cal-reticulin isoforms in the sera of pancreatic cancer patients (38). Le Naour et al. identified auto-antibodies reacting to Crt 32 in the sera of pancreatic cancer patients (39). The final goal of clinical cancer proteomics is to discover biomarkers for early small cancers, to clarify pathogenesis and carcinogenesis of cancers, and to tailor the therapy for the cancer patients. Although a huge number of reports about the discovery of biomarkers by proteomics has been published, still no biomarker is being used practically in hospitals. However, some kinds of proteins detected in sera from cancer patients are expectable as abiomarker (24,37,38,39).

Secreted Proteins Differentially Expressed in Prostate Cancer

The prostate secretes a range of proteins related to its function, including proteolytic enzymes, acid phosphatase (ACPP), and prostate-specific antigen (PSA). In prostate tumors, some of these proteins are known to increase or decrease in the amount secreted. To test the application of secretory vesicle isolation to frozen human surgical specimens, samples were obtained from patients with prostate cancer, with institutional review body (IRB) approval and patient consent. Tumor and normal tissue were separated as described 47 and the content of the secretory apparatus was isolated. Proteins were digested with trypsin and analyzed by LC-MS in order to compare expression between each normal and tumor pair from all six patients. Significantly differentially expressed peptides were identified. Four of the best known prostate cancer-associated secreted proteins were found to be up-regulated, as expected, in the tumors. PSA, ACPP, kallekrin 2 (KLK2), and macrophage migration inhibitory...

Androgens and Prostate Carcinogenesis

Results from the earlier summarized rodent experiments clearly indicate carcinogenic and strong tumor promoting properties of androgens, and the results of a limited number of epidemiological studies provide some support for the concept that androgens may have such effects in humans. The mechanisms of the carcinogenic and tumor-promoting effects of androgens on the rodent prostate are not known with certainty. The very steep relationship between testosterone dose and prostate carcinoma response in rat models suggests involvement of an androgen receptor-mediated mechanism 199 . However, other mechanisms may also be involved. For example, Ripple et al. 239 observed increased oxidative stress in androgen-sensitive LNCaP human prostate cancer cells exposed to DHT, but it is possible that these effects were androgen receptor-mediated.

Covalent Binding of Carcinogens to Tissue Macromolecules

The detection of the covalent binding of aminoazo dyes to liver protein in rats fed DAB and similar dyes (Miller and Miller, 1947) depended on the intense red color of these dyes in acid as a marker for the whole p-aminoazobenzene structure (Cilento et al., 1956). The protein-bound dye from DAB was the first identification of an adduct of a metabolite of a carcinogen to a macromolecule in a tissue undergoing carcinogenesis. The amount of these adducts correlated strongly with the carcinogenicities of DAB and its ring-methyl derivatives in the rat liver (Miller et al., 1949). Surprisingly, no protein-bound dye could be detected in the liver tumors caused by DAB, even during its administration. This led to a deletion theory of the mechanism of tumor formation by this carcinogen (E. C. Miller and Miller, 1947 J. A. Miller and Miller, 1953). Thus, if dye bound to proteins that controlled growth led to a loss of these proteins in certain cells, then these cells would become tumor cells....

Stimulation of Cell Proliferation and Carcinogenic and Tumor Promoting Effects of Androgens

Androgen receptor-mediated stimulation of prostatic cell proliferation by androgens has been implicated in human prostate carcinogenesis 135, 235 . However, there is no direct evidence that elevation of circulating testosterone leads to increased cell proliferation in the human prostate. Androgen administration to castrated rodents causes elevation of prostatic cell proliferation similar to that observed in cell cycle synchronization experiments with cells in vitro 240 . The increase in prostatic cell proliferation caused by androgen administration to castrated rodents is only transient, and after a few days cell turnover returns to its normal very low level 240 . Thus, continued androgen treatment of rodents does not result in constantly elevated rates of cell proliferation in the male accessory sex glands, but probably only supports differentiation. DHT may even suppress prostatic cell proliferation in intact rats 206 . Thus, continuous stimulation of cell proliferation is unlikely...

The Role of HDAC Family Members in Development and Cancer

As discussed later, several members of the HDAC family have been shown to be either aberrantly expressed or mistargeted in different tumors and are consequently potential targets for cancer therapy. Fortunately, HDAC inhibitors are relatively well tolerated by patients and do not lead to as dramatic side effects as the phenotypes of HDAC knockout mice would suggest. The contrasting phenotypes between genetic deletion and pharmacological inhibition might be explained by the following facts (1) While genetic deletion is permanent, HDAC inhibitors act transiently. (2) Ablation of HDACs leads to their outright inactivity, whereas their pharmacological inhibition might be incomplete. (3) As components of multisubunit complexes, certain deacetylases might have also nonenzymatic functions such as stabilization of corepressor complexes. Genetic deletion of HDACs results in their complete absence annihilating both the catalytic activity and their potential scaffolding function. In contrast,...

The Hallmarks of Cancer Revisited

One decade ago, Hanahan and Weinberg determined the six most important factors for cancer development and tumor progression (Hanahan and Weinberg 2000). Blocking of apoptosis and differentiation as well as the stimulation of angiogenesis, proliferation, and metastasis are commonly described as hallmarks of cancer and known to be regulated by epigenetic mechanisms including histone acetylation (Fig. 1). During tumorigenesis, the global pattern of histone acetylation is changed. For instance, cancer cells undergo a loss of acetylation at H4K16, suggesting a crucial role of HDAC activity in establishing the tumor phenotype (Fraga et al. 2005). In this chapter, we try to build a bridge between the previously established features of the multistep process of tumorigenesis and the wide-ranging contribution of HDAC family members to these mechanisms.

Hepatic Microsomal Metabolism of Carcinogens and Its Induction by Unrelated Chemicals

As noted by Trager (1980), the carcinogen DAB was the first xenobiotic to be studied in vitro for its metabolism by liver homogenates or microsomes. These studies by Mueller and Miller (1948) showed the 7V-demethyIation, reduction of the azo linkage, and aromatic ring-hydroxylation occurred on aerobic incubation of DAB with liver homogenates fortified with pyridine nucleotides and hexose diphosphate. Enzymatic reduction of the azo linkage was found predominantly in the microsome fraction (then called the small granule fraction) and was dependent on both NADPH and a flavin adenine dinucleotide-containing protein (Mueller and Miller, 1949, 1950). It was further shown that the enzymatic demethylation of 7V-monomethylaminoazo dyes depended on oxygen and NADPH with the formation of stoichiometric amounts of formaldehyde (Mueller and Miller, 1953). One of the substrates used in these studies was 3-methyl-4-monomethylaminoazobenzene (3-methyl-MAB). It proved to be very resistant to reduction...

Estrogens and Prostate Carcinogenesis

As summarized earlier, the results of epidemiological studies provide limited evidence for an association between prostate cancer risk and circulating levels of estrogens, which appear to be higher in African American men (under 50 years of age) than in European American men. This observation suggests that estrogens may be involved in prostate carcinogenesis, because men of African descent living in an American environment have the highest risk for prostate cancer world-wide. However, most direct evidence in support for a role of estrogens in prostate carcinogenesis is derived from studies with treatment of NBL rats with testosterone and 17 -estradiol 206,207,244 . The mechanisms involved in the prostatic effects in this model are a mixture of estrogen receptor-mediated and non-receptor processes. In addition, there is evidence to suggest that the mechanisms involved in hormonal induction of rat prostate carcinomas, which originate from the periurethral prostatic ducts, are different...

The Role Of miRNAs In Cancer Diagnosis And Drug Discovery

Recently, it has been reported that the expression of several miRNAs are altered in a variety of human cancers, suggesting potential roles of miRNAs in tumorigenesis (37). Calin et al. (38) showed that more than 50 of miRNAs were located in cancer-associated genomic regions or in fragile sites. In fact, miR-15a and miR-16 genes exist Cimmino et al. (40) found that both these miRNAs negatively regulate the expression of B-cell lymphoma 2 (BCL2), which inhibits apoptosis and is present in many types of cancers including leukemias. In fact, overexpression of miR-15 and miR-16 in the MEG-01 cell line induces apoptotic cell death. Alterations in the gene copy number of miRNAs are detected in a variety of human cancers (41,42,43). Zhang et al. (41) showed that miRNAs exhibited high-frequency ge-nomic alterations in human ovarian, breast cancer, and melanoma using high-resolution array-based comparative genomic hybridization. Hayashita et al. (42) found that the expression and gene copy...

BRCA1 Breast Cancer Susceptibility Gene Product

In the search for a mammalian homolog of Rad9, three proteins were found to share significant homology with the BRCT motifs of scRad9 - BRCA1, MDC1 and 53BP1. BRCA1 was identified in 1994 as the product of a gene that acted as a tumor suppressor in breast and ovarian cancer. Since then hundreds of mutations have been found in affected families and 80 of individuals carrying BRCA1 defects succumb to these diseases.

Impaired Apoptotic Responses Speed Up Carcinogenesis

Programmed cell death, or apoptosis, is one of the most extensively studied topics in the areas of basic biology and cancer. The apoptotic cell is characterized by membrane blebbing, cell shrinking, cytosolic and or nuclear condensation, and breakdown of chromosomal DNA. Apoptosis is vital to life in multicellular organisms during embryonic development and to help the removal of damaged cells in an orderly way to shape the organs and maintain adequate immune and neural cell populations. Upon invasion of exogenous pathogens, apoptosis is an important process to eliminate pathogendamaged cells. Therefore, the cellular apoptotic response has to be tightly regulated, as too little or too much apoptosis will lead to developmental deficiency, autoimmune response, or cancer.

National Cancer Institute Ncis 60cell Screening And Gene Expression Data

The National Cancer Institute's (NCI's) 60-cell line drug discovery panel (NCI60) was developed as a tool to assess anti-cancer activity of compounds against a range of cell lines derived from different cancers, including lung, renal, colorectal, ovarian, breast, prostate, central nervous system, melanoma, and hematological malignancies (12). Chemicals that reduce the viability of the cell are tagged as potential leads for affecting particular pathways characteristic of each tumor cell's biology. The biological response of such a cell-based assay is rich in information because, in principle, the complete systems biology information is encoded in the assay.

Linkage Between Silica And Lung Cancer

Mining, construction, sandblasting, farming, and other occupations. Environmental exposure to aerosolized fine silica is also a major public health issue. Although silica is now considered as a human carcinogen, the molecular mechanisms involved in silica-induced carcinogenesis remain to be answered, because evidence for carcinogenicity in humans and animals is still debated. Human epidemiologic studies have not conclusively documented evidence or a dose-response relationship regarding the role of silica as a potential carcinogen in many exposed population studies. Furthermore, animal exposure studies to silica are controversial, because silica shows species differences in carcinogenicity. In the rat, a single intratracheal instillation of silica induces lung tumors, i.e., mostly of adenocarcinomas associated with silicotic fibrosis. In mice and hamsters, on the other hand, similar exposure to silica does not produce characteristic fibrotic lesions or tumors.86 However, silica can...

Mechanisms Leading to Increased Growth and Survival Signalling in Breast Cancer Cells

Recent studies within our group have begun to define a previously unidentified role for zinc in contributing to ER dependent and independent forms of endocrine resistance through its capacity to sustain the activity of growth factor signalling. Zinc is a metal ion which is involved in the regulation of many cellular processes, including proliferation and survival, and increased zinc levels have been shown to inactivate several phosphatases involved in the dephosphorylation and inactivation of EGFR, HER2, IGF-1R and c-src (Haase and Maret, 2005). Exposure of our tamoxifen resistant cells to zinc, therefore, serves to activate signalling from these growth factor receptors and raise the intracellular activity of MAPK and AKT to promote tumour cell growth and motility (Taylor et al., 2008). Significantly, we have shown that acquired tamoxifen resistance in vitro is associated with increased basal zinc levels and increased expression of a key zinc transporter, ZIP7 (HKE4 SLC39A7), which...

ABC Transporters and Cancer Therapy

ABC transporters play an important role in multidrug resistance in cancer chemotherapy. Human ABC transporters are divided into five different subfamilies ABCA, ABCB, ABCC, ABCD and ABCG, based on phylogenetic analysis. According to the transport classification database (TCDB), these ABC transporter subfamilies (ABC-type efflux permeases) belong to subclasses 3.A.1.201-212 19 (http www.tcdb.org ). Transporters in subfamilies ABCA, ABCB, ABCC and ABCG are involved in multidrug resistance 96-99 .

Gene Profiles As Biomarkers For The Diagnosis And Classification Of Human Cancers

Gene profiling has proven quite valuable in identifying genes whose expression can be used to diagnose specific cancers, including many that are difficult to distinguish by other methods. For example, Kohlman et al. in 2003 used gene profiling to differentiate between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) 18 . Bone marrow samples were isolated from 90 patients, 25 having been diagnosed with ALL, and 65 with AML. RNA was extracted from the samples and labeled cDNAs hybridized to Affymetrix U95Av2 and U133 microarrays. The WV algorithm and the leave-one-out cross-validation approach were then used to identify a subset of genes that were expressed differentially between the two leukemias. The expression of 24 genes was then used to accurately identify patients with AML, while 19 The utility of the U133 arrays was studied further in the diagnosis of leukemia using 937 patients (892 with clinically relevant leukemia subtypes and 45 nonleukemic patients) 27 ....

Asbestos A Potent And Established Carcinogen

Animal and human epidemiologic studies indicate that inhalation of asbestos can cause serious respiratory diseases, including asbestosis, bronchogenic cancer, and mesothelioma.137 138 Exposure to asbestos has also been linked to certain types of tumors that originate in the stomach, throat, and rectum.139 People who are working with asbestos-containing products or who live near asbestos mining manufacturing areas also have a high risk of contracting asbestos-induced lung diseases.140 Asbestos refers to a family of crystalline fibrous silicates that are relatively indestructible, heat resistant, and have a high commercial importance. Serpentines and amphiboles are the two distinct varieties of asbestos with succinct physical and chemical characteristics of commercial importance in different applications. The serpentine asbestos (chrysotile) is curly and flexible and accounts for most of the asbestos used commercially in North America. Crocidolite, amosite, tremolite, and anthophilite...

Gene Profiles As Biomarkers Of Prognosis In Cancer Patients

Despite the problems associated with gene profiling approaches that were noted above, there have recently been significant advances in using gene profiling to predict prognosis in cancer patients. For example, van' t Veer and colleagues isolated at diagnosis 78 core samples from breast cancer patients under the age of 55 36 . Of these patients, all were lymph node-free at the time of diagnosis. By measuring patient outcome over five years (regardless of treatment regimen), it was observed that 34 patients developed distant metastases, whereas 44 patients did not. Microarrays containing 25,000 human genes were prepared by the investigators, to which labeled cDNA samples from the patients and a pooled reference RNA sample were hybridized. The utility of the van't Veer genes as prognostic biomarkers has been tested further using a larger study, which included 295 patients 13 . Sixty-one patient samples (from the study in which the 70-gene classifier was developed) were included as a...

Targeting Cancer Pathways

Cancer is essentially a disease arising from an accumulation of genetic abnormalities (60, 61, 62), which are thought to participate in neoplastic development and in some cases the development of chemotherapeutic resistance (63,64,65). Many genes have been implicated in the genesis of various cancers (60,66). In the process of carcinogenesis, some are found to be mutated, whereas others tend to exhibit dysregulated levels of expression (67, 68, 69, 70). Both mutation status and RNA or protein expression levels have proven valuable for the development of cancer diagnostic assays, particularly for prediction of prognosis. However, a diagnostic gene expression pattern does not necessarily have a causative role in carcinogenesis (71,72,73,74,75,76). A focused analysis on changes in the expression patterns of specific cellular pathways can reveal biological insights that are not easily apparent from variations in individual genes. We analyze gene expression data obtained from human tumor...

Ap1 A Molecular Switch For Asbestosinduced Carcinogenesis

Heintz et al.172 first demonstrated that asbestos activates AP-1 transcription factor by inducing persistent expression of c-fos and c-jun genes in rat pleural mesothelial cells and hamster tracheal epithelial cells. In AP-1-luciferase reporter transgenic mice, asbestos activates AP-1 in both lung and bronchial tissues.173 This activation of AP-1 by asbestos is persistent until day three after a single dose of crocidolite asbestos exposure. Further studies suggested that PKCa plays a critical role in asbestos-induced c-fos and c-jun expression, since a PKCa inhibitor substantially decreased c-fos and c-jun mRNA in asbestos-treated cells.174 In addition, asbestos is also capable of inducing expression of fra-1, a gene encoding another AP-1 subunit, Fra, in rat mesothelial cells in a dose-dependent manner.175 A recent study by Ramos-Nino et al.176 demonstrated that the fra-1 induction by asbestos in mesothelial cell transformation is dependent on the activation of extracellular...

Tumor Suppressor Genes In Hereditary Cancers

As described in Chapter 3, several recessively inherited syndromes caused by defects in DNA repair genes are associated with an increased cancer risk, often for leukemias and lymphomas ( Table 3.2). Other 'cancer syndromes' are inherited in a dominant mode. Most of these predispose to a restricted range of cancers or even to a single tumor type, while a few are rather unselective, e.g., the rarer Li-Fraumeni and Cowden syndromes (Table 5.1). Table 5.1. Some dominantly inherited cancer syndromes in man Table 5.1. Some dominantly inherited cancer syndromes in man Cancer site

Stability of Cancer Pathways

Cancer is a genetic disease and genes operate through pathways. Variations in the gene regulation patterns in a pathway, as reflected by the change of cohesiveness in the pathway, may be indicative of pathway instability, which itself may be a result (or cause) of genetic abnormalities. Approximately half of the 962 analyzed pathways contain at least one of the 346 known cancer genes according to a recent census of human cancer genes (60). A change in cohesiveness has been found in 25 of all the pathways analyzed, including both down and up pathways. The question is then whether the pathways that have shown a cohesiveness change in tumor compared to normal tissues can be considered to be cancer pathways based on the likelihood of them containing cancer genes, or whether cancer pathways in general are more likely to change their cohesiveness. The answer to the first questions is yes, because cancer genes are found in 57 of the pathways that have shown a change in their cohesiveness,...

Strategies to Target Change in Anti Cancer Therapies by Finding Agents That Can Potentially Perturb an Unstable Pathway

Pathways that tend to change their cohesiveness in tumor-containing versus normal tissues represent interesting targets for anti-cancer therapy, making it highly desirable to locate agents with the potential to specifically disrupt these pathways. The previously discussed relationship between compound cytotoxic response to pathways and MOAs through gene expression patterns can now be brought to bear on specific cancer pathway targets (58). Compound clusters derived from growth inhibition data (GI50) that are significantly correlated with a pathway can potentially perturb that pathway. Therefore, for each of the pathways with a change in gene expression coherence, we have found the SOM cluster that is associated with the pathway (58). Most notably, compounds clustered in clades P4 and M3 are associated only with up pathways, and those in clades N9, P6, F6, F8, and V1 are associated predominantly with down pathways and with very few or no up pathways. Most clinically used compounds in...

ER Negative Endocrine Resistant Breast Cancer

Current strategies for the treatment of ER negative endocrine resistant breast cancer, outside of conventional chemotherapy, are extremely limited. Some success has recently been derived from the increasing use of trastuzumab in women with HER2 over-expressing tumours, although this is a relatively small cohort of patients. Disappointingly, responses to gefitinib are similarly restricted, despite the elevated expression of the EGFR in many ER negative tumours. At presence two further approaches are being pursued. Firstly, considerable effort is being made to define the growth and survival pathways being used by these cells and our microarray and protein analysis have revealed a potential role for c-Met in ER negative, faslodex resistant breast cancer cells (see Chapter 8). This increase in c-Met confers a greatly increased sensitivity to exogenous HGF, which promotes their further invasiveness when stimulated by the exogenous ligand or by co-culturing cells with fibroblasts that...

Opioid rotation in chronic noncancer pain

The concept of OR is based largely on research and clinical experience in the treatment of cancer pain however, the technique may also be of benefit in CNCP127 or acute pain management.128 However, according to a Cochrane review, OR is still not practiced commonly if there are problems with opioid therapy in CNCP.129 I In a prospective review of patients commencing opioids for CNCP, the rates of OR at six months were 10.6 percent (controlled-release oxycodone), 19 percent (transdermal fentanyl), and 26.0 percent (controlled-release morphine sulfate), respectively.130

Receptor Tyrosine Kinases As Target For Anticancer Therapy

Overexpression and or structural alteration of RTKs' family members are often associated with human cancers, and tumor cells are known to use RTK transduction pathways to achieve tumor growth, angiogenesis, and metastasis. Thus, RTKs represent a pivotal cancer therapy target. Several small molecules acting as RTK inhibitors have been synthesized by pharmaceutical companies and are under clinical trials. Some are being analyzed in animal models or already have been successfully marketed. Cancer-homing toxins are a group of man-made cytotoxic molecules targeting cancer cells. These molecules contain toxins, natural or usually derivatives, connected to a cancer-homing module, such as a monoclonal antibody or growth factor or their derivatives. As mentioned earlier, 70 of SCLC express the kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Several studies determined that inhibitors of kit tyrosine kinase activity could have therapeutic efficacy in this disease....

Cancers of the Digestive System

Elevated levels of several HDAC family members have been reported in PDAC. Immunohistochemical analysis has revealed the presence of HDAC1 in 56 of tumor samples analyzed (Miyake et al. 2008). In addition, coexpression of HDAC1 and HIF-1a has been shown to correlate with poor prognosis (Miyake et al. 2008). Moreover, HDAC2 overexpression has been identified in a tissue microarray of pancreatic cancer (Fritsche et al. 2009), which has been linked to c-Myc (Marshall et al. 2010). Importantly, it has been shown that HDAC2 mediates the resistance of PDAC cells to the chemotherapeutic drug etoposide due to silencing of the proapoptotic NOXA gene (Fritsche et al. 2009). Furthermore, increased expression of HDAC7 has been reported in pancreatic cancer (Ouaissi et al. 2008). Elevated expression of two members of class I HDAC family has been demonstrated for gastric cancer. Increased levels of HDAC1 mRNA have been correlated to reduced expression of gelsolin and retinoic acid receptor p in...

Anticarcinogenic Potential of

A large number of laboratory studies have documented the chemo-preventive effect of tea, particularly green tea, against structurally diverse classes of chemical carcinogens as well as radiation-induced tumours (Table 8.1). Tea can suppress the carcinogenic response in many tissues. Moreover, Initiator of carcinogenesis Cancer site the anticarcinogenic effect of green tea is manifested at very low concentrations when the model carcinogen was -methyl- -nitrosourea, green tea extracts at the low concentration of 0.002 (w v) effectively decreased colon carcinogenesis induced by the nitrosamine (Narisawa and Fukaura, 1993). The strength of brews consumed by humans is about 2-3 . It appears that tea exerts its anticarcinogenic effect by modulating all stages of chemical carcinogenesis. In chemical systems, aqueous extracts of green and black tea prevented the formation of heterocyclic amines and the nitrosation of methylurea (Weisburger et al., 1994 Constable et al., 1996). Numerous...

Radiation Biology And Cancer

The biological effect of radiation on living cells tends to vary and depends on dose. It is well known that radiation is known to cause cancer, but in clinical practice, radiotherapy is an accepted form of cancer treatment. Injured or damaged cells may self-repair, die, or be involved in a misrepair process (see discussion later). High-radiation doses tend to kill cells, while low doses tend to damage or alter the genetic code (DNA) of irradiated cells. High-radiation doses can kill so many cells that tissues and organs are damaged immediately and tend to initiate a rapid body response, often called acute radiation syndrome. High-radiation dose manifests itself early. This was evident in many of the atomic bomb survivors in 1945 and in the emergency workers who responded to the 1986 Chernobyl nuclear power plant accident (Sali et al., 1996). Low doses of radiation over long periods may not cause immediate problems in body organs, but effects may occur at the cellular level. Genetic...

Contribution of caffeine to the anticarcinogenic activity of green tea

Caffeine (1,3,7-trimethylxanthine) is a major component of tea that may contribute to its anticarcinogenic activity. It is present in green and black tea, comprising 5 of all solids and in 1.25 (w v) brew is present at a concentration of about 220 g ml-1 (Wang et al., 1994). The ability of caffeine to modulate the tumorigenicity of chemicals is well documented. However, caffeine has been demonstrated to both inhibit and potentiate chemically induced cancers in rats and mice (Nomura, 1976 Hiroshino and Tanooka, 1979 Denda et al., 1983 Welsch et al., 1988a). Similarly, some epidemiological studies established correlations between coffee consumption and certain cancers (MacMahon et al., 1981 Boyle et al., 1984) whereas others failed to detect an association (Rosenberg et al., 1985 Wynder et al., 1986). A comparison of the anticarcinogenic potential of green and black teas with that of their decaffeinated derivatives against ultraviolet B (UVB) light-induced skin carcinogenesis in mice...

Effect of caffeine on the promotion stage of carcinogenesis

In studies conducted in female rats using the mammary carcinogen 7,12-dimethylbenz a anthracene, caffeine suppressed the carcinogenic response when administered during the initiation phase. However, it failed to attenuate the carcinogenic response when administered during the promotion stage (Welsch et al., 1988b Welsch and DeHoog, 1988) and even stimulated the carcinogenic activity in female mice (Welsch et al., 1988a). Clearly, caffeine is unable to influence the promotion stage of carcino-genesis and is even less likely to have such an effect when consumed as tea, where the level is relatively low.

Mechanism Based Carcinogenic Risk Assessment of Estrogens and Estrogen Like Compounds

Estrogens play an important role in mammalian reproductive cycles and a disturbance of this cycle can cause adverse effects like carcinogenicity.A mechanistic modeling approach is helpful in attempting to unravel the entanglement of genomic, non-genomic, and feedback signals involved in endocrine signaling. To make more balanced decisions on possible human health risks put forth by endocrine active compounds (e.g., estrogens and estrogen-like agents), a multidisciplinary approach is necessary. Besides traditional epidemiological studies, accumulation of mechanistic data is essential for all classes of agents. Combining all available information is a positive move towards a more complete risk assessment process. 4 Carcinogen Risk Assessment 119

Photodynamic Therapy Of Cancer

Photodynamic therapy (PDT) of cancer is based on the use of compounds that are able to absorb harmless visible light energy and transfer it efficiently to other molecules in their vicinity or alternatively use it for photochemical reactions with biomolecules.100 These compounds are normally known as photosensitizers (PS). After irradiation with light of the suitable wavelength, the PS molecules are excited from the ground state (1PS0) to a singlet excited state (1PS*) that can reverse to the ground state by nonradiative internal crossing (IC) or by fluorescent emission (F), the latter of which can be used for imaging and detection (photo-diagnosis). Alternatively, it may undergo an electronic rearrangement to the excited triplet state (3PS*) by intersystem crossing (ISC, Fig. 4.45). Most reactions of relevance to PDT take place in the triplet state, which must be sufficiently long-lived to give intermolecular reactions before its deactivation by emission of phosphorescence (P). In the...

Transcriptional Coactivators and Corepressors in Breast Cancer

A great deal of in vitro and in vivo evidence has emerged regarding the importance in particular of NCoAs and NCoR SMRT in breast cancer progression. Indeed, NCoA3, also known as AIB1 (Amplified in Breast Cancer 1) was originally identified following its cloning from a region of chromosome 20 that is amplified in breast cancer cells, and the AIB1 gene has been shown to be amplified in 5-10 of breast tumours (Anzick et al. 1997). Furthermore, transgenic mice over-expressing AIB1 develop mammary tumours, with 85 of the tumours being ERa-positive (Torres-Arzayus et al. 2004), suggesting that AIB1 is an oncogene. SRC2 TIF2 and CBP overexpression have been reported in breast cancer, compared with the normal breast (Kurebayashi et al. 2000 Girault et al. 2006). SRC1 levels have also been associated with shorter disease-free survival in breast cancer (Myers et al. 2004). Immunohistochemical analysis of 290 ERa-positive primary breast cancers showed that high levels of AIB1 are associated...

Deacetylation of Nonhistone Proteins by HDACs and the Implications in Cancer

Abstract Acetylation and deacetylation of lysine residues controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, are among the most common posttranslational modifications of proteins. In addition to histones, a large number of nonhistone proteins that can undergo reversible acety-lation have been identified. These nonhistone acetylated deacetylated proteins are involved in a wide range of cellular processes including transcription, translation, DNA repair, metabolism, and cell structure. Aberrant deacetylation of nonhistone proteins is implicated in many human diseases, including cancer. In this chapter, we review and describe the involvement of HDACs in cancer-associated cellular processes via deacetylation of nonhistone proteins, and the possible implications for carcinogenesis and cancer development. Keywords HDAC Histone deacetylase Nonhistone acetylation Nonhistone deacetylation Cancer H. Lee Moffitt Cancer Center & Research Institute,...

Modulatory Actions of Neuropeptide Y on Prostate Cancer Growth Role of MAP KinaseERK 12 Activation

Neuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Evidence exists that, among these molecules, the pleiotropic neuropeptide Y (NPY) and the related receptors may play a role in the normal prostate as well as in the progression of human PCa, which represents one of the most common malignant diseases among men in the Western world. The role of NPY in PCa biology appears to vary in different in vitro human PCa cell systems, since it has been found to reduce the proliferation of LNCaP and DU145 cells, but to stimulate the growth of PC3 cells. These effects are mediated mainly by the NPY Y1 receptor and are associated with a clone-specific pattern of intracellular signaling activation, including a peculiar time-course of MAPK ERK1 2 phosphorylation (long-lasting in DU145 and transient in PC3 cells). In conclusion, several studies support the concept...

Potential of Soyiso in the Prevention of Cardiovascular Disease and Cancer

Animal experiments have revealed the anticarcinogenic properties of SOYISO and soybean products (Messina et al., 1994 Helms and Gallaher, 1995 Lamartiniere et al., 1995). Genistein arrested the cell cycle at the G2-M phase while daidzein did so at the G1 phase (Jing et al., 1993 Matsukawa et al., 1993). Proposed mechanisms include oestrogenic and anti-oestrogenic effects (Adlercreutz, 1990 Messina and Barnes, 1991), induction of cancer cell differentiation, inhibition of tyrosine kinase in cell signalling (Messina and Barnes, 1991) and DNA topoisomerases in DNA replication (Markovits et al., 1989), and suppression of angiogenesis. But, as stated earlier, SOYISO can protect DNA from oxidative damage caused by UV or H2O2 FeCl2 and inhibit the H2O2 formation induced in cancer cell lines by the tumour promoter, TPA. These data demonstrate that the antioxidant activity of SOYISO may play an important role in their anticancer activity. It must be stressed that soybeans contain a variety of...

Phytoestrogens And Carcinogenesis

Almost all animals are exposed to an array of environmental chemicals, some of which can mimic the activities of endogenous hormones. Different plant products and synthetic compounds are known to have similar chemical compositions and act as estrogens.146 These estrogenlike compounds (so-called phytoestrogens), under laboratory conditions or in the natural environment, might be capable of causing a spectrum of adverse effects on the endocrine system that eventually cause several disorders, including tumorigenesis.147-150 Many in vitro studies using breast cancer cells indicate that phytoestrogens alone imitate the estrogenic effect and induce estrogen-dependent protein (pS2) and cell proliferation in ER-positive MCF-7 cells.146 However, in the presence of estrogen, the effect of phytoestrogens was reversed and the effect was not ER dependent.146 This issue remains a source of debate.151 Despite the adverse effects of naturally occurring phytoestrogens, these compounds also exhibit...

Mechanisms Of Diminished Apoptosis In Cancer

Diminished apoptosis of cancer cells is important for a number of reasons. (1) In some cancers decreased apoptosis is the primary cause of tumorous growth, e.g. in follicular B-cell lymphoma and perhaps in early prostate cancer ( > 19.1). In these tumors, cells that ought to undergo apoptosis in the course of normal tissue homeostasis survive, which leads to an oversized and progressively disorganized tissue mass. (2) A diminished rate of apoptosis exacerbates hyperproliferation in many different cancers. (3) Apoptosis is a fail-safe mechanism in response to 'inappropriate' proliferation signals (as is replicative senescence) and following pronounced DNA damage, e.g. unrepaired double-strand breaks. Therefore, a decreased response to 'internal' pro-apoptotic signals allows cells to proliferate in spite of proliferation signals being inappropriate or in spite of persisting severe DNA damage. This occurs in many cancer types, at the latest during progression. (4) Cytotoxic T-cells...

Dysregulation of EGFR in Lung Cancer

From early studies into EGFR function, and the identification of ErbB transforming genes in the avian erythroblastosis virus, there was a clear consensus that aberrant EGFR activity likely contributes to the etiology of a large subset of cancers (1). Focusing on lung cancer in particular, there had been early suggestions that abnormal EGFR gene regulation was a common phenomenon in non-small cell lung cancer (NSCLC), with approximately 50 of such cancers exhibiting EGFR over-expression at the protein level (35,36), with more recent studies placing the number at around 62 (37). In addition, frequent amplifications of the chromosomal 7p12 region, in which the EGFR locus is contained, had been documented (38). The clinical outlook for lung cancer is bleak. Worldwide, deaths due to the disease account for a third of all cancer-related deaths, making it the deadliest of all cancers. Lung cancer encompasses a number of diseases of diverse histological subtypes, the etiologies of which are...

Transcriptional Coregulators as Targets in Breast Cancer Treatment

That several coactivators and corepressors are likely to be important for endocrine response and resistance in breast cancer, in particular, the coactivators SRC1, AIB1 and the corepressors NCoR, SMRT. The importance of these proteins in crosstalk with growth factor signalling indicates that they may be important downstream targets of growth factor receptor and protein kinase inhibitors currently being evaluated in the clinic. In addition, SRC1 and AIB1 are subject to other modifications, in particular acetylation, ubiquitination and SUMOylation (Lonard and O'Malley 2007 Lonard and O'Malley 2008), with the modifications determining their activity and turnover, a better understanding of which may provide additional methods for drug development. As SRC1 and AIB1 appear to act by facilitating the recruitment of histone acetyltransferases, namely CBP p300 and P CAF, and the histone methyl-transferases CARM1 and PRMT1, small molecule inhibitors of these enzymes may provide additional...

Carcinogen Risk Assessment

Regulatory agencies need input from the scientific community to develop adequate policies with regard to potentially hazardous agents, such as EACs. The biological sciences aspect of the risk assessment process includes hazard identification (qualitative), providing information on effects caused in exposed individuals, and dose-response assessment (quantitative), linking the size of an exposure to the response. Estrogenic compounds in the environment have the ability to cause a variety of (adverse) effects in humans and wildlife. The focus here will be on the carcinogenic risk assessment for these agents.

Links Between Wholefood Antioxidants and Heart Disease Cancer and Vision Loss

Antioxidant deficiencies have well-established links to the promotion of specific diseases. This is discussed more fully in other chapters. Antioxidant compounds are accumulated from the diet or synthesized in the body and prevent the chemical oxidation of proteins, lipids and other essential compounds. Industrialization has led to increased environmental pollutants in our air, food and water. Many of these pollutants have the capacity to deplete the body's antioxidant reserves. Antioxidant deficiencies resulting from dietary deficiencies and or increased environmental oxidant stress may be linked to the development of many diseases including heart disease, cancer and vision loss. Damage to cellular regulatory proteins and DNA is central to the promotion of cancer in humans. Oxidation is a primary means by which this damage occurs and antioxidants from our food may have the ability to protect against cancer promotion. Analysis of antiproliferative effects of whole-food products also...

Flavonoids and Cancer

Animal studies in rodents have demonstrated that flavonoids have anticar-cinogenic efficacy in reducing the number of chemically induced tumors and the growth of implanted cancer cell lines.62 The most probable chemopre-ventive mechanisms of action include modulating cytochrome P450 enzymes to prevent carcinogen activation and increasing the expression of Phase II conjugating enzymes to facilitate carcinogen excretion.63 Some flavonoids also appear to have the capability of reducing cell proliferation by inhibiting protein kinase C and AP-1-dependent transcriptional activity to block growth-related signal transduction.64 Yet other flavonoids can limit the initiation of cancer cells by stimulating DNA repair systems.65 A dozen prospective and case-control studies in Finland, the Netherlands, and the United States have found no consistent trend and association between flavonoids and cancer risk for any forms of cancer or for total cancers.66 However, the twenty-four-year follow-up data...

Ra Expression in the Normal Breast and Breast Cancer

In the progression to breast cancer, cells increase their level of ERa expression, and ERa levels seen in breast cancer are consistently higher than those seen in normal breast (Panahy et al., 1987 Silvistrini et al., 1979). Increased ERa expression is seen in the earliest stages of ductal hyperplasia, and increases even more with progressing atypia - in cases of atypical ductal hyperplasia and in low to intermediate grade ductal carcinoma in situ (DCIS), most of the ductal epithelium stains ERa-positive (Allred et al., 2001 Shoker et al., 1999b). Another early change observed in the progression to malignancy is the loss of the inverse relationship between ERa expression and cell proliferation, especially as ERa expression becomes more widespread (Shoker et al., 1999a). Atypical ductal hyperplasia (ADH) and low grade CIS demonstrate strong ERa-positivity, with immunohistochemical analysis revealing contiguous ERa-positive cells in a majority of the lesion (Roger et al., 2000 Shoker et...

Antiproliferativeantitumoranticancer activity

Synytsya et al. (2010) demonstrated the antitumor activity of fucoidan from Undaria pinnatifida in PC-3, HeLa, A549, and HepG2 cancer cells in similar pattern to that of commercial fucoidan. In addition, fucose-rich sulfated polysaccharide of E. cava has antiproliferative effects on murine colon carcinoma (CT-26), human leukemic monocyte lymphoma (U-937), human promyelocytic leukemia (HL-60), and mouse melanoma (B-16) cell lines (Athukorala et al., 2009). Fucoidan was found to inhibit proliferation and induce apoptosis in human lymphoma HS-Sultan cell lines (Aisa et al., 2004). Further, they have reported the fucoidan-induced apoptosis was accompanied by the activation of caspase-3. In another recent study, antitumor and antimetastatic activities of fucoidan, isolated from brown seaweed Fucus evanescens, were studied in C57Bl 6 mice with transplanted Lewis lung adenocarcinoma (Alekseyenko et al., 2007). Another in vitro study demonstrated the inhibitory effects of fucoidan on...

Breast Cancer Resistance Protein

The role of BCRP (or ABCG2) seems to be to protect tissues by actively transporting toxic substances and xenobiotics out of the cells. Cancer cells overexpressing ABCG2 show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been observed in oral availability and clearance of drugs that are substrates for ABCG2, especially topotecan (73). Genetic variation in the ABCG2 gene could possibly explain the variability in pharmacokinetics of ABCG2 substrates. SNPs have already been reported in the ABCG2 gene (74-76). In AML cells, ABCG2 is overexpressed however, the association between the expression and clinical resistance to anticancer drugs remains undetermined (81,82). The identification of functional sequence variation in the ABCG2 gene could also be of interest in the field of prognosis of disease. In conclusion, to date no in vivo effects of BCRP polymorphisms...

N2hydroxypropylmethacrylamide Hpma Copolymers For The Delivery Of Anticancer Agents

The use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. The covalent binding of low molecular weight drugs to water-soluble polymer carriers offers a potential mechanism to enhance the specificity of drug action. The major distinction between low molecular weight anticancer drugs and their macromolecular conjugates is the mechanism of cell entry. While low molecular weight drugs may penetrate into all cell types by diffusion, their attachment to macromolecules such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, limits cellular uptake of the polymer-drug conjugates to the endocytic route. Internalized macromolecules are then transferred via endosomes into the lysosomal compartment of the cell. 10 The rate of (fluid-phase) pinocytosis is low. Consequently, in normal tissue the polymer-drug conjugate is largely confined to the bloodstream. 11 However, the abnormal tissue vasculature found in tumors allows the...

Cancer Stem Cells Discovery and Evidence of BTSC

Approximately 150 years ago pathologists Rudolph Virchow and Julius Cohnheim suggested there were histological similarities between the developing fetus and certain cancers (such as teratocarcinomas) and that both tissues have the capacity to differentiate and proliferate. This embryonal-rest hypothesis is the historical version of today's cancer stem cell hypothesis.4 As defined at the American Association for Cancer Research workshop on cancer stem cells cancer stem cells are cells that1 self renew and2 resupply the tumor with the various lineages of cells of which it is comprised. Selfrenewal can only be defined experimentally by the ability to recapitulate the generation of a continuously growing tumor-or tumor initiation cell (Fig. 1).5,6 Figure 1. Overview of tumor stem cells in cancer. Cancer stem cells (tumor-initiating cells) divide asymmetrically, resulting in self-renewal of the tumor-initiating cell and production of a daughter cell known as a transient-amplifying cell...

HPMA copolymerAnticancer Agents Currently in Human Trials

Presently there are seven polymer-drug conjugates which have entered Phase I II clinical trials as anti-cancer agents in the U.K (five of which are HPMA copolymer-drug conjugates). These include N-(2-hydroxy-propyl)methacrylamide (HPMA) copolymer doxorubicin (PK1, FCE 28068), HPMA copolymer-paclitaxel (PNU 166945), HPMA copolymer-camptothecin, PEG-camptothecin, poly(glutamic acid)-paclitaxel, HPMA copolymer-platinate (AP 5280), and HPMA copolymer-doxorubicin conjugates bearing galactosamine (PK2). The rapid proliferation of HPMA copolymer anti-cancer agents is evidence of the promising potential of HPMA copolymer carried agents.

Ovarian Cancerbenefits Of Hpma Copolymer Conjugation

Doxorubicin (adriamycin), a well studied anticancer agent, has shown efficacy in the treatment of human ovarian epithelial carcinoma. 26 Doxorubicin acts by reversibly stabilizing covalent adducts between topoisomerase II and DNA and additionally generates free radicals. These activities result in DNA breaks, cellular membrane damage and cell death. 27, 28

Zinc Status and Its Relevance to Cancer

The role of zinc in cancer has received increasing attention. The link between zinc deficiency and cancer has been established in human, animal and cell culture studies. Zinc status is compromised in cancer patients compared to healthy controls.85,86 Zinc deficiency causes oxidative DNA damage87 and chromosome breaks have been reported in animals fed a zinc-deficient diet.88 In rats, dietary zinc deficiency causes an increased susceptibility to tumor development when exposed to carcinogenic compounds.89 93 Zinc deficiency has also been suggested to be a contributor to the development of esophageal tumors in rats.91,92,94 In vitro, cell culture studies have also shown that zinc deficiency can lead to increased oxidative damage to testicular cell DNA.95 Together, these data strongly suggest that zinc deficiency itself compromises the integrity of DNA and may increase one's risk of developing cancer. However, the exact molecular mechanism by which zinc deficiency impacts DNA integrity...

Current Standard Of Care For Metastatic Colorectal Cancer

Until the year 2000, the only systemic therapy for metastatic CRC was a bolus or infusional 5-FU regimen, mostly in combination with leucovorin (5-FU LV), achieving a median survival of 12 month (20). However, over the last 6 years many new agents have been developed and approved by the Federal Drug and Food Administration (FDA) for the treatment of mCRC (7). A summary of the current guidelines for treating colorectal cancer is shown in Table 1. Irinotecan (CPT-11), a prodrug of SN 38, achieves its anti-carcinogenic effect through inhibiting topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA (21). Oxaliplatin is a platinum analog that inhibits DNA synthesis through the formation of intra-strand DNA adducts and is currently approved by the FDA for use both in adjuvant and metastatic settings (22). CPT-11 and oxaliplatin, when combined with 5-FU LV based chemotherapy regimens, have boosted response rates (RR) and overall-survival (OS) to 50 and at least 16 months,...

Cancer and Metastasis

Most of the adhesion receptor families reported so far, including inte-grins, cadherins, selectins, immunoglobulins, and proteoglycans, have been implicated in various stages of tumor progression and metastasis. Integrins allb (33 and aL 32 and immunoglobulin family members PECAM-1, ICAM-1, and N-CAM in solid tumor cells are some examples of such adhesion molecules (Tang and Honn, 1994). Changes in the adhesive properties of solid tumour cells, such as downregulation of desmosomal proteins (e.g., plakoglobin) and neo-expression of ICAM-1 or MUC18, have also been suggested to be important determinants of the metastatic capability of individual malignant cells (Pantel et al., 1995). The importance of adhesion molecules in tumor metastasis is also evidenced by their involvement in other important parameters of metastasis such as angiogenesis (Tang and Honn, 1994). An increase in oxidative stress markers such as oxidized DNA and compromised antioxidant have been reported in several types...

Chemokines and Cancer

Most cancers express an extensive network of chemokines and che-mokine receptors (Balkwill & Mantovani, 2001 Vicari & Caux, 2002). Selected chemokine receptors are often upregulated in a large number of common human cancers, including those of the breast, lung, prostate, colon, and melanoma (Tanaka et al., 2005 Vicari & Caux, 2002). Tumor-associated chemokines have at least five roles in the biology of primary and metastatic disease (Murphy, 2001) (1) control of leukocyte infiltration into the tumor, CCL2 is one of the most frequently detected CC chemokines in cancer (Mantovani et al., 2004), high levels of CCL5 are expressed stage II and III cancer (Luboshits et al., 1999 Yaal-Hahoshen et al., 2006) (2) manipulation of tumor immune response, regulatory T cells express the chemokine receptor CCR4 and are attracted into ovarian cancer by tumor- and macrophage-derived CCL22 (Curiel et al., 2004) (3) regulation of angiogenesis, CXC chemokines regulate angiogen-esis either...

Zinc and prostate cancer

Etiologic factors that initiate and enhance the progression of prostate malignancy are beginning to emerge. One major research focus is the role of diet and nutrition. Dietary factors possibly linked to prostate cancer are numerous however, the most provocative data focus attention upon those nutrients and phytochemicals involved in oxidative defense. A clear understanding of how anti-oxidants may protect the prostate from the genetic damage that is associated with tumor development remains unclear. It is well established that the consumption of fruit and vegetables is associated with reduced risk of many cancers.133,134 These strong and reproducible epidemiological associations have led to an interest in determining the specific components within whole foods responsible for this observed reduced risk. However, supplementation with certain anti-oxidant compounds has not been successful. The anti-oxidant -carotene which when provided as a dietary supplement to populations at high risk...

Human carcinogenicity data

Because of a few early cases of urothelial cancer among Belgian patients suffering from Chinese herb nephropathy, individuals with end-stage renal disease were offered prophylactic nephroureterectomy. This surgical procedure led to the identification of a high prevalence of pre-invasive and invasive neoplastic lesions of the renal pelvis, the ureter and the urinary bladder in patients with Chinese herb nephropathy. The number of malignancies detected (18 cancers in 39 women undergoing prophylactic nephroureter-ectomy) greatly exceeded the expected number of these uncommon tumours. There was a positive dose-response relationship between the consumption of the herbal mixture and the prevalence of the tumours. Some cases of clinically invasive disease have been described in the follow-up of end-stage Chinese herb nephropathy patients not undergoing prophylactic nephroureterectomy. Subsequent phytochemical investigation led to the identification of aristolochic acids in the herbal mixture...

Blocking Chemokines and or Chemokine Receptors as Approaches to Cancer Therapy

Targeting specific chemokines derived from tumors that may affect tumor angiogenesis are a promising area for the future. Antibodies to neutralize CXCL5 and CXCL8 reduced tumor growth, vascularity, and metastasis in experimental models of nonsmall-cell lung cancer (Arenberg et al., 1998, 1996). Neutralizing antibodies to CCL20 inhibited the growth of prostate cancer cells that overexpress CXCR4 in a tumor xenograft model (Beider et al., 2009). Higher expression levels of selected chemokine receptors have been reported in many cancer cells compared to their normal counterparts. A partial list includes, for breast (CXCR3, CXCR4, CCR7, CXCR7, CCR5),ovarian (CXCR4), prostate (CXCR4, CXCR5, CCR9, CCR5, CX3CR1), pancreas (CXCR4, CXCR1 2, CCR6), bladder (CXCR4), colon (CXCR3, CXCR4, CCR6, CCR7, CXCR1 2), stomach (CCR7), and thyroid (CXCR4) (Wu, Lee, Chevalier, & Hwang, 2009). It appears that three receptors, CCR7, CXCR4, and CXCR7, are prominently expressed in cancer and more specifically...

Combination Doxorubicin And Pdt For Ovarian Cancerbenefits Of Hpmacopolymer Conjugation

In vitro studies using HPMA copolymer-bound doxorubicin and Mce6j in combination, have demonstrated a 10-fold increase in each drug concentration to be equally or more effective than free drug in the models used. These in vitro findings suggest the potential attenuation of combined nonspecific toxicities through HPMA copolymer conjugation. 54 This has been subsequently established in vivo. 33 Using a mouse model of ovarian cancer, HPMA copolymer delivery of doxorubicin or Mce resulted in a 2-30 fold increase in the free drug equivalent dose delivered without increasing the nonspecific toxicity of either drug. 33 The combination of HPMA copolymer bound doxorubicin and Mce6 resulted in significantly reduced Figure 6. Combination chemotherapy and PDT of OVCAR-3 tumors heterotransplanted in nude mice treated with HPMA copolymer-bound anticancer drugs control (- -) P-C (12.5 mg kg, 1.5 mg kg Mce6 equivalent) with light (-0-) P-A (30 mg kg, 2.2 mg kg Doxorubicin equivalent) (- -) P-A (30 mg...

Epigenetic Hallmarks of Cancer

Salser's observation in 1977 that 5mC was responsible for the mutation of CpG dinucleotides prompted investigators to determine whether the natural patterns of methylation were disturbed in human neoplasia.14 The first change to be reported for a number of cancers by Andrew Feinberg and colleagues was loss of methylation at the level of individual genes and globally.108,109 In four of five patients, representing two different types of cancer, Southern blots revealed substantial hypomethylation in genes of cancer cells compared to their normal counterparts in one of these patients hypomethylation was progressive in a metastasis.108 Such a loss appeared to be ubiquitous for human neoplasms, whereas hypomethylation was the only type of change observed in benign neoplasms. A generalized decrease in genomic methylation was also noted as cells age, and this gradual loss could result in aberrant gene activation. The second notable change observed in many human cancers was hyperme-thylation,...

Significance of Faulty Imprinting in Cancer

Feinberg and colleagues attached special significance to LOI in cancer and they initiated a search for the mechanism by which this epigenetic change might enhance the risk to neoplasia. In the first of two papers, Cui et al. found that LOI of the insulin-like growth factor II (IGF2) gene, a feature common to many human cancers, occurred in about 10 of the normal human population.117 LOI in this segment of the population increased the risk of colorectal cancer about 3.5-to 5-fold, suggesting that faulty imprinting was related to the risk of cancer. In the second paper, Sakatani et al. created a mouse model to investigate the mechanism by which LOI of Igf2 contributed to intestinal cancer.118 They knew from the work of others that imprinting of Igf2 was regulated by a differentially methylated region (DMR) upstream of the nearby untranslated H19 gene, and that deletion of the DMR would lead to biallelic expression (LOI) of Igf2 in the offspring. To model intestinal neoplasia, they used...

Histone Modifications of Cancer Cells

Considerable effort has been devoted to understanding the relevance of aberrant DNA methylation patterns to human cancer, but much less attention has been focused on histone modifications of cancer cells among many other layers of epigenetic control. Recently, Mario Fraga and colleagues120 characterized the profile of posttranslational modifications of one of the nucleosomal core histones of chromatin, histone H4, in a comprehensive panel of normal tissues, cancer cell lines, and primary tumors. Using immunodetection, high-performance capillary chromatography, and mass spectrometry, Fraga found that cancer cells overall lost monoacetylation at H4-Lys-16 and trimethylation of histone H4-Lys-20. These are widely regarded as epigenetic markers of malignant transformation, like global hypomethylation and CpG island hypermethylation. In a mouse model of multistage carcinogenesis, these changes appeared early and accumulated during the tumorigenic process. They were also associated with...