Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

Undergoing chemotherapy can be one of the most terrifying things that you go through in your life. One of the most frightening things about chemotherapy is the lack of real information that most people have about it, and the unknown makes it so much more frightening as a result. This eBook, written by a young cancer survivor gives you the real story about what chemo is all about. The most valuable information you can get about chemotherapy is from someone that has already experienced it. This PDF eBook allows you to download and read it as soon as your order it. You can begin your journey of reassurance as soon as you want! Because that's what this is about: chemo does not have to be a terrifying unknown! Other people have gone through it before, and want to help you through it as well! This eBook is the guide through chemo that many people wish they could have had, and now you can have it yourself! More here...

Chemo Secrets From a Breast Cancer Survivor Overview


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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 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...

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.

Assessment of Apoptotic Tumor Response with 99mtcAnnexin A5 Following a Single Dose of Chemotherapy in Comparison with

Successful chemotherapy or radiotherapy induces apoptosis in neoplastic cells and indicates tumor response to the therapy 30-32 . Determining baseline levels of apoptosis and the increase of apoptosis induced by therapy can serve as useful prognostic markers 33, 34 . Annexin A5 (annexin V) is an endogenous protein that binds with high affinity and specificity to PS, which is presented on the cell surface in the early process of apoptosis. Accordingly, apoptotic cells can be detected in vivo using annexin A5 labeled with radionuclides, such as 99mTc 14, 18, 20, 21 . Accordingly, we applied apoptotic imaging with 99mTc-annexin A5 to the assessment of apoptotic tumor response following a single dose of chemotherapy, and compared it with FDG in rats with implanted hepatomas.

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.

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...

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...

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...

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...

The Medical History of Current TB Chemotherapy

Effective chemotherapy for tuberculosis began in 1940s with the discovery and use of streptomycin (STR, Fig. 1 1a) and para-aminosalicylic acid (PAS, Fig. 1 2a) 7-9 . The first randomized controlled study of STR treatment for TB by the British Medical Research Council (BMRC) showed that streptomycin was effective in the short term but that ultimately so many patients developed STR-resistant TB and hearing loss that at 5 years, no net clinical benefit was seen 10 . Contemporaneously, PAS was found to be bacteriostatic against MTb (including STR-resistant strains) in experimental models and able to prevent the development of STR The 1950s were significant because of the discovery and initial use of isonizaid (INH, Fig. 1 3a). There were several trials to optimize treatment combinations of INH with STR and PAS. Although INH was generally well tolerated in patients, some experienced rash or hepatitis with this drug. INH treatment led to rapid improvement over the first month of therapy,...

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...

Where Do We Go From Here in the Treatment of ERaBreast Cancer

We have demonstrated the ability to re-express ERa in ERa-breast cancer cells via the inhibition of hyperactive MAPK resulting from overexpression of EGFR or erbB-2 in both established ERa-breast cancer cell lines as well as ERa-tumors. This re-expression of ERa can be achieved via either direct inhibition of MAPK or via inhibition of the upstream growth factor receptor (EGFR or erbB-2) that is driving its hyperactivation. We have also established that the restoration of ERa expression is sufficient to induce anti-estrogen responses in a subset of these ERa-breast cancer cells. Clearly then, strong signaling via MAPK directly represses ERa expression and ERa signaling is known to repress the expression of both EGFR and erbB-2. It is apparent that in breast cancer, the co-expression of high level signaling from both receptor types is mutually exclusive. A clue for why this co-expression is not tolerated by breast cancer cells comes from our own studies as well as those of others. Upon...

The Dark Side of Antihormonal Action in Breast Cancer

Abstract Antihormones are of substantial benefit in treating oestrogen receptora positive (ER+) breast cancer. However, their anti-tumour effect is limited by emergence of resistance. Our in vitro studies are highlighting a new underlying concept that antihormones are not passive bystanders but alongside growth inhibitory effects promote adverse compensatory mechanisms within tumour cells. These mechanisms involve drug-induction of signalling elements normally suppressed by oestrogen (E2)-occupied ER While best exemplified by the tyrosine kinases epidermal growth factor receptor and HER2, microarrays reveal the true diversity of the induced signalling kinases, where their potential to promote resistance is exacerbated under paracrine conditions. Such drug-induced events permit initial ER+ breast cancer cell survival, allow development and maintenance of resistance, and also promote gain of invasiveness under conditions of poor intercellular contact. In addition, prolonged antihormonal...

BRCA1 DNA Damaging Chemotherapy and Antimicrotubule Drugs

HCC1937 breast cancer cells with a single copy of mutated BRCA1 were much more sensitive to a range of DNA damaging agents in comparison with HCC1937 cells reconstituted with wild-type BRCA1. In the same cell line model, BRCA1 also induced sensitivity to the antimicrotubule drugs paclitaxel and vinorelbine (57). These data suggest that BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis depending on the nature of the cellular stress (40). BRCA1 dysfunction might be an Achilles heel for testing new drugs. Inhibitors of poly(ADP-ribose) polymerase (PARP) highly sensitize tumor cells harboring BRCA1 dysfunction (62,63). Breast cancer patients carrying BRCA1 mutations attain better response to anthracycline-based chemotherapy than patients without mutations (64).

Clinical Trials Of Customized Chemotherapy

ERCC1 has been associated with cisplatin resistance, providing a testable hypothesis for customizing therapy. From August 2001 to October 2005, 444 stage IV NSCLC patients were enrolled in a Spanish Lung Cancer Group randomized trial of customized chemotherapy based on ERCC1 mRNA levels. RNA was isolated from pretreatment biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Results were available in 8 days. Patients in the control arm received docetaxel plus cisplatin. Patients in the genotypic arm received treatment based on ERCC1 mRNA levels those with low levels received docetaxel plus cisplatin those with high levels received non-cisplatin-based treatment (docetaxel plus gemcitabine) (90). The primary endpoint was the overall objective response rate. Of the 444 patients enrolled in the study, 78 patients (17.6 ) went off-study prior to receiving one cycle of chemotherapy. The main reason for withdrawal was...

Chemotherapy And Immunotherapy Of Renal Carcinomas

Renal cell carcinomas are notoriously difficult to treat by chemotherapy or radiation therapy. Several factors may contribute to this 'primary' resistance. (2) Excretion of toxic compounds is an important functions of the normal kidney. Tumor tissues from this organ retain some of the protective systems of the kidney and in particular the excretion system involving the 'PGP glycoprotein' MDR1 (Figure 15.9). MDR1 is an ATP-dependent transport protein ('ABC' transporter) which helps to exchange lipids between the inner and outer leaflet of the cell membrane. This reaction also allows the excretion of a broad range of lipophilic cytostatic drugs from the cell. In this fashion, the protein contributes to multi-drug resistance in many human cancers. In other cancers, its expression is acquired or induced only after exposure to chemotherapy, leading to 'secondary' chemoresistance. In the kidney, in contrast, the MDR protein is normally expressed at high levels, likely to support the...

D Nrti Combination Chemotherapy

The most widely used NRTI combination is AZT+ 3TC. This combination is now available as a single formulation, Combivir, which reduces the dosage to one pill taken twice daily, a significant improvement over the multiple dosing regimen required for administration of the drugs in individual formulations. AZT+3TC combinations have certain therapeutic advantages. The dual-drug regimen significantly delays the development of AZT resistance compared to that noted with AZT alone (Larder et al., 1995). Perhaps more importantly, the M184V associated with 3TC resistance restores AZT sensitivity to AZT-resistant HIV-1, despite the continued presence of AZT resistance mutations (Larder et al., 1995). Recent studies indicate that the M184V mutation eliminates the increased rate of pyrophos-phorolysis associated with the D67N K70R T215F K219Q AZT-resistant RT, thereby restoring chain-terminating activity to AZT (Gotte et al., 2000). This restoration of AZT sensitivity may be one of the reasons for...

Current Challenges In Breast Cancer Treatment

Breast cancer is the most common cancer among women. There were an estimated 240,510 new breast cancer cases and an estimated 40,910 breast cancer deaths in the United Stated in 2007 (1). For the past decade, the overall risk of mortality due to breast cancer has been declining with the development of advanced therapies as well as advance in early detection (2). However, the survival rate has not been substantially improved for patients with recurrent or metastatic breast cancer (3). The main reason is that the current criteria to predict breast cancer progression and clinical outcome are unable to accurately classify breast cancer patients into subgroups of good prognosis and poor prognosis, reflecting a different probability of disease recurrence and survival after therapy (4). In this regard, another unsolved challenge is to create standards to guide clinicians in deciding which combination of treatments is most suitable for each individual patient. It has been proven that breast...

Traditional Prognostic Factors For Breast Cancer

Substantial efforts have been made to establish the predictive factors for patients with breast cancer during the last two decades. The traditional predictive factors are age, lymph node status, tumor size, histologic type, tumor grade, lymphatic vessel invasion, and hormone receptor status (10). With the development of molecular biology and cell biology, many new predictive factors have been created, including markers regulating cell cycle and cell death, Her2 neu, markers of metastasis or metastatic processes, lymph node micrometastases, bone marrow micrometastases, and markers of angiogenesis (11). Although the traditional predictive factors lack information about the biological diversity of breast cancer and do not reflect the complexity of molecular mechanisms of these diseases, they are still the most valuable criteria for clinicians to decide the relevant therapies (12). For instance, Adjuvant Online ( is a prognostic system based on traditional...

Estrogens And Androgens In The Treatment Of Breast Cancer

Antagonizing the effects of estrogen in breast cancer frequently is effective, and the use of antie-strogens such as tamoxifen is now a standard part of hormonal therapy of breast cancer. immuno-histochemical detection of estrogen receptors (ER) and progesterone receptors (pR) has improved selection of patients for hormone therapies. Most patients with ER- or pR-positive tumors will respond to hormonal therapy these patients also have a better overall prognosis independent of the type of therapy. in contrast, ER- and pR-negative carcinomas rarely respond to hormonal therapy. Clinically detectable responses to hormone therapy usually take 8-12 weeks to detect. If the disease responds or remains stable on a given treatment, the medication typically is continued indefinitely until the disease progresses or unwanted toxicities develop. The duration of an induced remission averages 6-12 months but sometimes can last for many years.

Etiology Of Breast Cancer

With colon cancer and increasingly lung cancer, breast cancer constitutes the trias of major cancers in females in Western industrialized countries. In these countries, the life-time risk of breast cancer is around 10 for women, and about 30 of them turn out to be lethal. Most breast cancers become apparent in women after their menopause, but a significant fraction is diagnosed earlier. In Western countries, the mean age at menopause is now 50 yrs, and menopause takes place in almost all women between 45 and 55. In females aged 40-60 years, breast cancer is the most frequent lethal cancer. In most countries, its incidence is rising, although the increase in mortality has been checked. There are several explanations for this phenomenon, invoking earlier detection and better treatment ( 20.4). In any case, it is generally agreed that certain aspects of the Western life style favor the development of breast cancer. There is much less agreement on which aspects these are (Table 18.1)....

Hereditary Breast Cancer

At least seven genes are now known, in which inherited mutations in one allele conduce a high risk of breast cancer (Table 18.2). Mutations in most tumor suppressor genes account for a small proportion of all familial cases, certainly less than 10 , while a larger fraction of familial breast cancers originates from mutations inactivating the BRCA1 and BRCA2 tumor suppressor genes. syndrome. This rare dominantly inherited disease is characterized by multiple benign hamartomas and by thyroid cancers, but also includes an increased risk for breast cancer. Mutations in the TP53 gene ( 5.3) are the cause of most cases of the rare Li-Fraumeni syndrome. In line with the general importance of the TP53 protein in the control of genomic stability ( 6.6), this is a generalized cancer syndrome which also includes a particularly high risk for breast cancer. A minority of cases might be caused by mutations in genes encoding the checkpoint kinases CHK1 and CHK2 ( 3.3). The more frequent HNPCC...

Classification Of Breast Cancers

Like other carcinomas, breast cancer is treated primarily by surgery. While formerly radical mastectomy with removal of all lymph nodes around the tissue constituted the standard approach, today's philosophy is to keep the surgical intervention as minimal as possible without risking a recurrence. Breast cancer metastasizes to local lymph nodes as well as to distal organs such as bone, lung, and liver. At the time of surgery, the extent of distal metastasis is often difficult to determine, because many metastases are too small to be discovered by imaging methods and no reliable molecular assays are available for the detection of breast cancer micrometastases. Therefore, if any significant risk of metastasis is assumed, chemotherapy is applied following surgery. Such 'adjuvant' treatment very likely prevents recurrences in some patients, but constitutes an over-treatment for those without metastases. Nevertheless, it is not always efficacious, since some The most important goal of...

Endocrine Resistance in Breast Cancer Where Are We Now With Intelligent Combination Therapies

Abstract Despite the improvements in breast cancer brought about by endocrine therapy, their success clinically is limited by a significant number of patients which continue to acquire resistance and die of the disease. An increased understanding of the various biological mechanisms responsible for the development of endocrine resistance has identified new therapeutic targets, providing the rationale for combining signal transduction inhibitors with endocrine therapies to delay the emergence of acquired resistance and enhance the efficacy of current endocrine treatments. Although therapeutic targeting of mTOR, Ras activation and erbB family members alongside the ER have shown promise in pre-clinical models, clinical results have been disappointing, partly due to poor patient selection. The application of rigorous trial design and tumour selection criteria to future clinical trials may allow more accurate evaluation of intelligent combination therapies in breast cancer patients. S....

The Treatment of Breast Cancer

A number of breast cancers are estrogen dependent. The estrogens, e.g. estrone 7.38 or estradiol involved in breast cancer are produced locally. There are a number of targets including the biosynthesis, the transport of the estrogen and the estrogen receptor. Inhibition of the biosynthesis of these steroids is an important chemotherapeutic target. The estrogens possess an aromatic ring A and this is formed from an androgen, androst-4-en-3,17-dione 7.35 or testosterone. Aromatase is the key enzyme system involved in this stage of the biosynthesis and it operates by the sequence 7.35-7.38. The oxidation of the methyl group to form 7.36 involves a cytochrome P450 system. Considerable work has been done to design selective inhibitors. The iron of the cytochrome is complexed by azoles such as anastrazole (Arimadex ) 7.39 and letrazole (Femara ) 7.40. Glutethimide 7.41 is another inhibitor, which binds to the iron of the cytochrome.

Chemotherapyinduced neuropathic pain

While this type of neuropathic pain can respond in the same way to treatment as any other type of neuropathic pain, the patient has the twin burdens of the cancer illness and disability produced as a temporary side effect of chemotherapy to endure, and so the imposition of neuropathic pain treatment related side effects needs to be avoided if at all possible. Therefore, the simpler the treatment the better. Particular treatments stand out in this respect. The dietary supplement L-carnitine has the advantages of a low risk of producing side effects and a relatively high chance of helping. Time to effect is also sort. Anecdotal evidence would also suggest that IV lidocaine and oral lamotrigine can both be efficacious and relatively well tolerated by the patient.

Molecular Mechanisms Of Cancer Chemotherapy

Topoisomerase inhibitors Etoposide exemplifies a third class of compounds which bind and inhibit enzymes involved in DNA replication. Etoposide specifically binds to topoisomerase II and blocks the enzyme at a critical stage. Topoisomerases are necessary for DNA replication (as well as for transcription), since they relax the torsional stress that is caused by the unwinding of the DNA helix. Topoisomerase I enzymes reversibly insert a single-strand break, allow the DNA strands to swivel around each other, and re-ligate the strand-break. Inhibitors of topoisomerase I used in cancer chemotherapy comprise innotecan, irinotecan and topotecan. Topoisomerase II enzymes catalyze a more dramatic reaction, in which a double strand break is reversibly introduced and another DNA helix (or a distant part of the same helix) is passed through, before the ends are resealed by the enzyme (Figure 22.3). This is a more fundamental reaction, which in addition to relaxing torsional stress allows the...

Project Title Adjuvant Ginseng Use During Breast Cancer Drug Therapy

Summary (provided by applicant) Ginseng is an herb widely used by humans to treat lack of stamina, loss of appetite and cachexia, and impotence. In Asian medicine, ginseng is a common component in herbals used in treatment of cancer, including breast cancer. There is recent scientific evidence that ginseng and its ginsenoside components are effective in inhibiting breast cancer cell proliferation in vitro and tumor growth in vivo. Consequently, many patients may be taking ginseng supplements during treatment with standard chemotherapy and hormonal therapy regimens in an effort to enhance therapeutic results as well as ameliorate side effects of the cancer chemotherapeutic drugs. However, there is no information on how adjuvant ginseng use could influence the efficacy of the cancer therapeutic drugs. This R21 proposal will address the following questions. Will the adjuvant use of ginseng aid in or interfere with standard breast cancer chemo- or hormonal therapy Will adjuvant ginseng...

Are Stem Like Cells Responsible for Resistance to Therapy in Breast Cancer

Abstract There is increasing evidence suggesting that some tumours originate from a stem cell population. Such observations appear to support the hypothesis that tumours can be generated and maintained by a small subset of undifferentiated cells able to self renew and differentiate into the bulk tumour population. Recently, cells with cancer stem cell-like properties have been identified within breast cancer tissues suggesting that a proportion of breast cancers may originate from such progenitors. Moreover, the intrinsic resistance of cancer stem cells (CSCs) to a range of chemotherapies suggests that their presence in breast cancer may also play a significant role in the development of an endocrine-resistant state. Future clarification of the role that CSCs play in such tumours, particularly in the context of therapeutic resistance, may lead to new treatment strategies for breast cancer where targeting of the CSCs specifically could lead to better and more sustained responses. S....

Restoration of ERa Expression and Anti Estrogen Responses in ERaBreast Cancer Cell Lines and Primary Cultures via MAPK

Using established ERa-breast cancer cell lines, the SUM 229s which overexpress EGFR, SUM 190s which overexpress both EGFR and erbB-2, and SUM 149s which model inflammatory breast cancer and have very high levels of RhoC leading to hyperactivation of NFkB in addition to EGFR overexpression, we have recently demonstrated that inhibition of MAPK activity could result in restoration of ERa expression (Bayliss et al., 2007). In fact, inhibition of MAPK activity via the pharmacologic MEK inhibitor U0126 results in significant levels of ERa expression in each of the 3 cell lines (Fig. 3.4A-C). To extend these data further, we have also established primary cultures from ERa-breast tumors. In all 3 ERa- primary tumor cell cultures we examined, inhibition of MAPK activity (even the relatively short inhibition in DT5s) is sufficient to restore ERa expression in these cells (Fig. 3.5). In DT13s, which overexpress ErbB-2, herceptin is also effective in restoring ERa Fig. 3.4 ERa re-expression upon...

Breast Cancer Resistance Protein Bcrp Abcg2

The ABC transporter BCRP was first cloned from a doxorubicin-resistant MCF7 breast cancer cell line (MCF-7 AdrVp) by Doyle et al. (1998). Subsequently, other groups cloned the BCRP cDNA sequence from other sources and designated the gene either MXR (mitoxantrone resistance protein) or ABCP (placental ABC protein) (Allikmets et al., 1998 Maliepaard et al., 1999). Since structural and sequence homology revealed that BCRP belongs to the ABCG gene subfamily, the Human Genome Nomenclature Committee conferred the official designation as ABCG2 (Table 7.1). BCRP consists of six putative TMD involved in drug binding and efflux, as well as a single amino-terminal cytosolic NBD that functions as an ABC involved in ATP hydrolysis. BCRP has been suggested to be a half-transporter that may function as a homodimer or tetramer bridged by disulfide bonds (Xu et al., 2004). Table 7.4. Partial list of compounds shown to interact with breast cancer resistance proteins

The Medicinal Chemistry of Tuberculosis Chemotherapy

Abstract The development of effective chemotherapy for the treatment of tuberculosis (TB) began in the 1940s and has been reinvigorated recently due to concern regarding the emergence of highly drug-resistant TB strains. This chapter explores the medicinal chemistry efforts that gave rise to current frontline and second-line drugs in global use today and attempts to comprehensively summarize ongoing discovery and lead optimization programs being conducted in both the private and the public sector. TB has a large number of disease-specific considerations and constraints that introduce significant complexity in drug discovery efforts. Conceptually, the disease encompasses all the drug discovery challenges of both infectious diseases and oncology, and integrating these considerations into programs that often demand collaboration between industry and academia is both challenging and rewarding. 1.2 The Medical History of Current TB Chemotherapy

Brief Account Of The Role Of Chemistry In Cancer Chemotherapy

Since the 1950s, chemistry has also generated many antitumor drug leads through in vitro screening programs promoted by the National Cancer Institute (NCI) in the United States by using a range of cancer cell lines. In this early period, transplantable rodent tumors models characterized by a high growth rate were used for in vivo screening. Later on, human tumor xenografts, based on transplantation of human tumor tissue into immune-tolerant animals, became also important tools for selecting antitumor drugs because the xenograft models allowed to simulate a chemotherapeutic effect under conditions closer to man. In the late seventies and early eighties, the role of chemotherapy was extended to preoperative and postoperative adjuvants, radiosensitizers to enhance radiation effects, and supportive therapy to increase the tolerance of the organism toward toxicity.14 Although DNA continues to be an essential target for anticancer chemotherapy, much recent effort has been directed to...

Chemotherapyinduced mucositis

1 Oral rinse with doxepin hydrochloride. Among the first reports of a local, peripheral analgesic effect of the tricyclic antidepressants was with oral doxepin rinse with cancer chemotherapy related mucositis. The pain relief produced may be due to the actions of tricyclic antide-pressants on sodium channels, opioid, and adenosine receptors, all of which are found peripherally. Despite its sodium channel blocking effect, this is not sufficient to compromise the protective glottic reflexes.

Breast Cancer

Breast cancer is the most common cancer of women living in Western populations 92 . The incidence of disease and death from breast cancers in the US and Western Europe substantially exceeds rates observed in most of Southeast Asia 93-95 . Incidence and mortality rates of breast cancer in Chinese and Japanese women in Asia are reported to be significantly lower than those of Chinese and Japanese women living in the US. The age-adjusted death rates from breast cancer are 2- to 8-fold lower in Asian countries than in the US and Western Europe 96 . This difference in breast cancer incidence has been correlated with differences in dietary patterns 93 . A large body of literature, including epidemiological, human, animal, and in vitro data, supports a beneficial role for dietary estrogens, particularly as a protective agent against breast cancer. Migration studies have indicated that the differences in these rates are dissipated after one generation following emigration from Southeastern...

Cancer Chemotherapy

The aim of this chapter is to show how cancer chemotherapy exploits the the role of specific inhibitors of particular developmental processes such as aromatase inhibitors of estrogen biosynthesis in the treatment of breast cancer. Cancer is one of the major causes of death and one of the most feared of diseases. The term covers a range of diseases of multi-cellular organisms linked by the common feature of an abnormal, poorly regulated and often invasive growth of the organism's own cells. The tumourous growth of tissue may be benign or it may be malignant and producing secondary growths known as metastases. Chemotherapy is one of a number of treatments for cancer that also include surgery and radiation and it is often used in combination with these. Useful drugs for cancer chemotherapy have to exploit the small differences between cancerous and normal cells. Many drugs target various aspects of DNA synthesis and hence act during the S phase of the cell cycle. Others interfere with...

Oestrogen Action and its Coupling to Growth Factor Signalling

In each instance, the cellular actions of ERa (subsequently referred to as ER) are productively linked to growth factor signalling cascades to orchestrate growth and survival signalling. Interference with such ER signalling using anti-hormonal drugs has both anti-ER and anti-growth factor actions, while aberrant growth factor signalling can sustain breast cancer cell growth in the presence of anti-oestrogens and in an oestrogen withdrawn environment (Nicholson and Gee, 2000).

Interactions of ER with Other Signalling Elements at the Cell Membrane

Interestingly, ER directed non-genomic responses (like nuclear ER responses) also rely on co-regulatory proteins that may be influenced by various signal trans-duction elements and one of these is believed to be over-expressed in some breast cancers. This protein (MNAR modulator of non-genomic activity of ER PELP 1 proline-, glutamic acid-, and leucine rich protein 1 ) enhances ER directed nuclear and membrane signalling (Vadlamudi et al., 2001 Wong et al., 2002) and contains c-src activating domains which directly activate ERK MAPK when in association with ER (Barletta et al., 2004). Controversially, other membrane associated proteins, such as GPR30, appear also to bind oestrogens with low affinity and instigate some signalling via EGFR transactivation. In breast cancer cells, however, GPR30 knockdown does not effect oestrogen signalling (Pedram et al., 2006) and their contribution of endocrine response and resistance is not considered further.

Selective Oestrogen Receptor Modulators SERMs

Early pharmacological studies using drugs such as tamoxifen, toremifene and ralox-ifene quickly established that they possessed mixed agonistic and antagonistic activity and that this varied considerably within oestrogen target tissues such as the breast, uterus and bone. In human breast cancer, SERMs are believed to be predominantly antagonists, although their limited agonistic activity has been linked to the phenomenon of tumour flare (Reddel and Sutherland, 1984) and may be exaggerated by excessive growth factor signalling to form a resistance mechanism (see below). Importantly, while SERMs are generally considered to be effective inhibitors of oestrogen-dependent AF-2 activity, they are considerably less effective on ligand-independent AF-1-mediated transcriptional responses (Tzukerman et al., 1994). The relative expression of AF-1 and AF-2 dependent genes within varying tissues (and potentially within breast cancer samples) may thus go some way to rationalising the mixed...

Oestrogen Deprivation

Fundamentally, oestrogen deprivation of breast cancer cells differs from their treatment with anti-oestrogens since the latter involves ER occupancy while the former does not. This is not just esoteric since unoccupied ER is largely an inactive molecule bound to heat-shock proteins, whilst on ligand binding such proteins are released and the ER may, in the case of SERMs, be subject to varying degrees of activation. This not only applies to nuclear ERs, but also to membrane localised ER whose activation is believed to be highly dependent on ligands (Levin and Pietras, 2008). Theoretically, therefore, oestrogen deprivation should be a highly effective treatment for oestrogen dependent breast cancer, although it is currently unclear how complete oestrogen loss needs to be to maximise such responses and whether ER occupancy by other ligands (e.g. phyto-oestrogens or androgens) can compensate for the decreased availability of more classical oestrogens.

Mechanisms Associated with Endocrine Resistance

It is evident from the above that a complex bi-directional cross-talk exists in endocrine responsive breast cancer cells between ER and growth factors to sustain growth and survival signalling and that anti-hormonal drugs are able to differentially effect elements of such signalling to promote growth inhibition (Nicholson and Gee, 2000 Nicholson et al., 2007). Clinically, however, while disease control by anti-hormonal drugs offers disease free and survival benefits, they do not work in all patients and responses in others are at best transitory (Bedard et al., 2008). Experimentally, data is described which indicates that such resistance can occur in ER dependent and ER independent forms through both genetic (De Laurentiis et al., 2005) and drug-induced (Gee et al., 2006) alterations in growth factor signalling within breast cancer cells and more detailed descriptions of its individual components are described below.

ER Dependent Mechanisms Growth Factor Pathway Switching

As mentioned above, a feature of breast cancer cells expressing high levels of growth factor receptors is that they often show evidence of an increased activity of several downstream protein kinases involved in signal transduction. These include MAPK (Knowlden et al., 2003), AKT (Jordan et al., 2004 Beeram et al., 2007), PAK-1 (Holm et al., 2006, Rayala et al., 2006), PKA (Michalides et al., 2004) and c-src (Chu et al., 2007 Hiscox et al., 2006c), which are able to directly or indirectly promote the activation of ER signalling components. They may also show elevated DNA binding activity of transcription factors, such as AP-1 which, depending on the balance of nuclear co-regulators, can use tamoxifen ER complexes to aid signalling through alternative response elements (see Section 1.2.2). Since cells genetically engineered to express highly activated forms of these signalling elements often show de novo resistance to tamoxifen (PAK1, Rayala et al., 2006 AKT, Clark et al., 2002, Beeram...

ER Independent Endocrine Resistance

Src-dependent activation of signal transducer and activation of transcription (STAT) 5b which did not require ER signalling and was thought to be involved in the development of the endocrine resistant state. Similarly, Iorns et al. (2008) have shown that CDK10 silencing in an RNAi screen of breast cancer cells increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumour cell reliance upon oestrogen receptor signalling (see Chapter 9). Such data are consistent with ER being merely supportive of the dominant growth factor pathway in anti-hormone-resistant cells, rather than always being essential for it. As an alternative to the above, ER-independent breast cancer growth can also be readily achieved by providing hormone sensitive or endocrine resistant cells with exogenous growth factors, circumventing the need for ER driven growth factor production (or making the consequences of it redundant). Several classes of growth factor appear to be able...

New Generalised Model of Endocrine Resistance

Since each of these elements are mechanistically linked to the regulation of the cell cycle and the survival of breast cancer cells, it is not surprising that they are often shared between de novo and acquired endocrine resistant models, are brought about by either genetic aberrations in growth factor signalling cascades or through adaptive mechanisms and result in either ER dependent forms of endocrine resistance, where the ER is harnessed to the altered growth factor signalling mechanism, or ER independent forms, where it is not.

Conclusions and Future Perspectives

Endocrine therapy is a well established and valuable approach to the treatment of breast cancer. Although resistance mechanisms to these therapies emerge during breast cancer development and treatment, they appear to be dominated by aberrations in growth factor signalling cascades which can drive breast cancer growth in an ER dependent or independent manner. As our molecular knowledge of these events expands, so too will our capacity to intervene. Inevitably this will improve the survival of breast cancer patients.

Mechanisms of Estrogen Receptora Action

ERa is a member of the nuclear receptor (NR) superfamily of transcription factors that acts primarily as a sequence-specific DNAbinding protein to regulate the expression of estrogen-responsive genes (Mangelsdorf et al. 1995 Chawla et al. 2001). Regulation of gene expression by ERa requires its recruitment to estrogen-regulated genes by direct binding to estrogen response elements (ERE), or indirectly through interaction with other transcription factors, for example AP1 and Sp1, prominent examples of the latter type of estrogen-regulated genes being the cyclin D1 and c-Myc genes (Bjornstrom and Sjoberg 2005). Recent studies using chromatin immunoprecipitation (ChIP) microarray (ChIP-chip) analysis, in which DNA sequences to which ERa is bound following estrogen stimulation in the MCF-7 breast cancer cell line are profiled using genomic DNA microarrays, show that as few as 4 of the ERa binding sites map to the proximal promoter region, with the majority of ERa binding sites located at...

Progress in the Treatment of Proliferative Lupus Nephritis

Summary Lupus nephritis (kidney inflammation associated with systemic lupus erythematosus, or SLE) is often well developed at the time of diagnosis. This article reviews progress in the treatment of proliferative lupus nephritis. High dose corticosteroids are universally accepted as the initial approach to the control of severe inflammation in the kidney. Long term disease control and the minimization of iatrogenic (physician caused) risk usually require adjunctive therapies that target the more fundamental immunoregulatory disturbances of lymphoid cells. Of the available cytotoxic drugs, cyclophosphamide is currently among the most effective, although it cannot be considered ideal in terms of efficacy or toxicity. New prospects for the treatment of proliferative lupus nephritis include novel immunosuppressive agents (e.g., mycophenolate, cyclosporine, fludarabine), combination chemotherapy (e.g., cyclophosphamide plus fludarabine), and sequential chemotherapy (e.g., cyclophosphamide...

Cross Talk Between ERa Coregulators and Growth Factor Receptor Signalling Cascades

There is now substantial evidence linking growth factor receptor signalling, in particular via the EGF receptor, HER-2 neu and IGF receptor pathways, with endocrine resistance in ERa-positive breast cancer (Dowsett et al. 2005 Gee et al. 2005 Os-borne et al. 2005). These findings have led to the proposal that inhibitors of cell surface receptor activation, for example using the EGFR inhibitor gefitinib Iressa, lapatinib or herceptin, or using inhibitors of downstream protein kinase cascades, in particular the PI3K AKT and MAPK pathways may be valuable treatments for endocrine resistant breast cancer. Interestingly, patients with ERa-positive breast cancer with high-level expression of AIB1 that are also HER2-positive have the worst prognosis (Shou et al. 2004). A similar relationship has been reported for EGFR HER1 with AIB1, as well as for HER3 with AIB1 (Kirkegaard et al. 2007). Together, these data suggest that crosstalk between cell surface receptors, ERa and AIB1 is important for...

Involvement of Other Transcriptional Coregulators in Estrogen Signalling

Approximately 300 NR coregulators have been described in the literature. In addition to the coactivators and corepressors discussed above, one or more of these potential coregulators may play important roles in breast cancer progression. Likely to be important for estrogen action in the breast are the corepressors RIP140 and L-CoR. Unlike NCoR SMRT, RIP140 and L-CoR are recruited through interaction with the NR ligand binding domain through a-helical motifs having the consensus sequence Leu-Xaa-Xaa-Leu, normally found in coactivators such as SRC1. Hence, these corepressors are recruited by the estrogen-bound ERa. Although there is no evidence to indicate that RIP140 and L-CoR are required for the regulation of estrogen-responsive genes whose expression is stimulated by ERa, it is important to note that the majority of estrogen-regulated genes in breast cancer cells are those whose expression is repressed by estrogen. Another ERa corepressor, ZNF366, which binds to the ERa DNA binding...

The ERaNegative Phenotype is Associated with UpRegulation of ErbB Family Members

ERa-tumors are characterized by a more aggressive phenotype, a poor prognosis, and a lack of response to hormonal therapies. It has been demonstrated that most ERa-negative breast cancer cell lines such as MDA-MB-231 cells, MCF-7 Adr cells, and MDA-MB-468 cells exhibit site specific methylation of CpG islands in the ERa promoter, and that reversion of this ERa-negativity requires treatment with a demethylating agent such as 5-aza-cytidine (Ferguson et al., 1995 Ottaviano et al., 1994). About 25 of ERa-negative breast tumors were found to exhibit hyper-methylation of the ERa promoter (Lapidus et al., 1996). More recent data using a highly sensitive methylation-specific PCR assay determined that 100 of these same ERa-negative tumors displayed some degree of methylation, however a number of ERa-positive tumors also showed similar degrees of methylation (Lapidus et al., 1998). More recently, it has also been demonstrated that histone deacetylation can maintain repression of ERa and this...

Hyperactivation of MAPK Results in Down Regulation of ERa Expression and This Down Regulation is Reversible

Using cell line models obtained by the stable transfection and overexpression of various signal transduction factors into ERa+ MCF-7 breast cancer cells we have shown that hyperactivation of MAPK, as a result of EGFR or c-erbB-2 overexpression activation, results in the downregulation of ERa protein and mRNA (El-Ashry et al., 1996 Liu et al., 1995 Miller et al., 1994 Oh et al., 2001). This downregulation is a dynamic event, reversible through the abrogation of MAPK (ERK 1 2) signaling - either via pharmacologic inhibition, through expression of dominant negative forms of ERK1 and ERK2 (Oh et al., 2001), or as a result of knockdown of ERK1,2 expression with siRNAs specific to each ERK. Shown schematically in Fig. 3.1 and quantitatively in Table 3.1 is the ERa and MAPK activity status of these cell lines. These cell lines, expressing a constitu-tively active c-Raf-1 (yielding (ca)Raf cells), a constitutively active MEK-1 construct (yielding (ca)MEK cells), a wild type EGFR which can be...

Influence of the Tumour Microenvironment

5.4.3 Model of ER Positive Breast Cancer Lymph Node S. Hiscox et al. (eds.), Therapeutic Resistance to Anti-Hormonal Drugs in Breast Cancer, DOI 10.1007 978-1-4020-8526-0.5, Springer Science+Business Media B.V. 2009 Keywords Breast cancer Fibroblast IGFs Interleukin 6 HGF Tumour microenvironment In view of its role in normal breast it would not be surprising that alterations in the nature and dynamics of the stromal microenvironment would be of major importance in breast malignancy. Dvorak (1986) considered tumour stroma to resemble wound healing except that physiological controls were not maintained. Previously tumour characteristics relating to the stroma were used to categorise breast cancers -Scirrhous carcinomas (Willis 1967). It is only more recently that studies have begun to address the importance of the microenvironment in tumour initiation, progression and metastasis (Liotta and Kohn 2001 De Wever and Mareel 2003 Weaver and Gilbert 2004 Barcellos-Hoff and Medina 2005 Hu and...

Macrophages Lymphocytes

There are differences in the populations of macrophages and lymphocytes between normal breast and breast cancers (Zuk and Walker 1988 Bhan and DesMarais 1983), and certain types of breast cancers e.g. medullary medullary-like are associated with a prominent lymphocytic infiltrate (Jacquemier et al. 2005). Macrophages secrete many cytokines and other proteins (Table 5.2) that can promote tumour growth and invasion. Tumour necrosis factor alpha (TNF-a), has cytotoxic and apoptotic activities but expression in breast cancer relates to metastasis (Miles et al. 1994). Its tumour-promoting functions may relate to its ability to promote Metalloproteinase expression and angiogenesis (Balkwill 2002). TNF-a (along with Interleukin-6, see Section 8.3.3) can also regulate oestrogen synthesis with in breast by increasing the activity of estradiol 17p hydrosteroid dehydrogenase and estrone sulfatase (Purohit and Newman 2002). The extracellular matrix (ECM) provides a scaffold for epithelial cells...

Hepatocyte Growth Factor

Hepatocyte Growth Factor (HGF) Scatter factor (SF) is a multifunctional cytokine that is produced by stromal cells (Jiang and Hiscox 1997). It acts in a paracrine fashion and activates the c-Met receptor protein. This promotes loss of cell-cell adhesion and enhanced cell migration. C-Met expression has been demonstrated in breast cancers and associated with poorer outcome (Lee et al. 2005 Leyngel et al. 2005). Recent data on Fulvestrant (pure anti-oestrogen) resistant breast cancer cells shows that they have increased motility and invasive capacity (Hiscox et al. 2006). Microarray comparisons found enhanced expression of c-Met. Stimulation by HGF SF secreting fibroblasts enhanced their aggressive phenotype which was suppressed by neutralisation knockdown of c-Met. The effects on invasion was seen with exogenous HGF, fibroblast conditioned medium or co-culture with fibroblast cells. This suggests that breast cancer TAFs could enhance the metastatic advantage of cancers that develop...

Modulating the Association ofHSP90 CoChaperones

The observations described above have been attributed to altering the ATPase activity of HSP90 by reducing AHA1 association (Holmes et al., 2008). Another obvious strategy is to target the co-chaperones involved in recruiting the client proteins to the HSP90 complex. HSP70 has a well documented role during the early stages of substrate loading onto HSP90 (Wegele et al., 2004). It is also implicated in malignant transformation due to its antiapoptotic role (Mosser and Morimoto, 2004 Calderwood et al., 2006). We have used an siRNA approach to selectively and simultaneously reduce the expression of the major constitutive and inducible isoforms of the HSP70 family, HSC70 and HSP72, respectively. We have shown that simultaneous knockdown of both isoforms inhibits the activity of HSP90 to induce degradation of CRAF, CDK4 and ERBB2 in human colon and ovarian cell lines (Powers MV, Clarke PA and Workman P, unpublished observations). This was accompanied by inhibition of cell growth and...

Adverse Features of Acquired Antihormone Resistance and Their Targeting

8.3 Endocrine Resistant Breast Cancer Cells Overexpress Cell Surface Receptors that May Sensitize them to the Tumour 8.4 Src Kinase as a Therapeutic Target in Breast 8.4.4 Targeting Src in Endocrine-Sensitive Breast 8.4.5 Targeting of Src in Endocrine-Resistant Breast Cancer Abstract Endocrine therapy is the treatment of choice in hormone receptor-positive breast cancer. However, the effectiveness of these agents is limited by the development of drug resistance, ultimately leading to disease progression and patient mortality. Cell models of endocrine resistance have demonstrated a role for altered growth factor signalling in the development of an endocrine insensitive phenotype. Significantly, recent studies have revealed that the acquisition of endocrine resistance in breast cancer is also accompanied by the development of an adverse cellular phenotype, with resistant cells exhibiting altered adhesive interactions, enhanced migratory and invasive behaviour, and a capacity to induce...

Interaction with EGFR Family Receptors

Physical interactions between Src and growth factor receptors are reported in breast cancer tissues and cells, particularly with receptor tyrosine kinases of the erbB family, known to be overexpressed in endocrine-resistant cell lines and tissues. Both EGFR and HER2 are frequently over-expressed in breast cancers (up to 60 , (Nicholson et al., 2001)), often with concomitant Src overexpression (Biscardi et al., 2000 Ishizawar and Parsons, 2004 Summy and Gallick, 2003). Indeed, Synergism between Src and the EGFR enhances neoplastic growth of mammary epithelial cells (Biscardi et al., 2000 Maa et al., 1995) and elevated expression of both EGFR and Src occur in a subset of late-stage breast cancers where interaction between these two molecules promotes an aggressive disease phenotype (Biscardi et al., 1998). Activation of Src following HER2 stimulation promotes cellular invasion through a mechanism involving FAK and the production of proteases (Mitra et al., 2006 Vadlamudi et al., 2003)...

Effect of TAMs on Cancer Cells

Angiogenesis is required for tumor growth, progression, and metastasis 73, 74 . Several studies have demonstrated that a high intratumoral MVC correlates with tumor advancement, systemic metastasis, and prognosis in several human cancers, including melanoma, breast cancer, colon cancer, and lung cancer 75-78 . Angiogenesis is a complicated process that involves the degradation of the basement membrane and invasion of the stroma by endothelial cells, which then proliferate, migrate, and become organized into a capillary structure 79 . This process is regulated by the local activity of a variety of angiogenic factors, such as IL-8, VEGF, and basic fibroblast growth factor (bFGF) 74, 80, 81 . Our previous study 82 demonstrated that the presence of infiltrating macrophages in sections from lung cancer patients is accompanied by increased levels of IL-8 mRNA and positively correlated with tumor angiogenesis and negatively with patient survival.

Interaction with Steroid Hormone Receptors

In addition to its genomic action, however, it is becoming clear that the ER can also exert rapid, non-genomic effects which are initiated in the cytosolic membrane compartment of the cell (Acconcia and Kumar, 2006). Activation of distinct cyto-plasmic protein kinase cascades in this manner results in the regulation of numerous cellular processes such as proliferation, differentiation, apoptosis and vasorelax-ation. In human breast cancer cells, ligand binding to the ER results in the rapid activation of the ERK and Akt pathways in a Src dependent manner (Migliaccio et al., 1996 Castoria et al., 2001 Wessler et al., 2006). Furthermore, in both ER-positive breast cancer cells and in cells which transiently express ER, oestradiol has been shown to induce rapid (within minutes) activation of Src-dependent signalling pathways (Castoria et al., 2001 Migliaccio et al., 1996) which regulate cellular proliferation and survival (Castoria et al., 1999 Migliaccio et al., 2000). The physical...

Identifying Modifiers of Tamoxifen Sensitivity Using High Throughput Genetic and Chemical Screens

Abstract Endocrine therapies, which inhibit estrogen receptor a (ERa) signalling, are the most common and effective treatments for ERa positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance. The precise mechanisms underlying endocrine therapy resistance remain incompletely understood. In our laboratory, an RNA interference (RNAi) screen was used to identify modifiers of sensitivity to the most commonly used endocrine therapy, tamoxifen. The cyclin-dependent kinase 10 (CDK10) gene was identified as an important determinant of resistance and the mechanism whereby this gene modulates sensitivity to tamoxifen was investigated further. Silencing of CDK10 gene expression was shown to activate the MAPK signalling pathway, circumventing the reliance of breast cancer cells upon estrogen signalling. Patients with ERa positive breast tumours that express low levels of CDK10 were shown to relapse early on tamoxifen and methylation of the...

Global View on Changes in Gene Expression in Cancer Cells After Interaction with TAMs

Analysis further supported the idea that IL-6, IL-8, M-CSF, MMPs, and ICAM-1 are involved in the NF-kB pathway 96, 97 . Because inflammatory cells may be involved in regulating the production of angiogenic factors by cancer cells, anti-inflammatory agents may have the potential to impede IL-8 induction and suppress angiogenesis initiated by inflammatory cells. Some nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, have been shown to reduce the risk of developing colorectal and breast cancers 98, 99 . We have tested several anti-inflammatory drugs commonly used clinically in our previous studies and found that most inhibit the expression of angiogenic factor IL-8 16, 82, 86 . Although their possible mechanisms of action are quite different 100-105 , their inhibitory effect is, for the most part, finally mediated through the NF-kB pathway (Fig. 4). On the basis of the above results, TAMs might therefore be a potential target of chemotherapy using anti-inflammatory agents.

Implication of TAMs in Immunotherapy of Human Cancers

Treated with biological response modifiers). Asano et al. 110 showed that liposomal MTP-PE increased cytokine expression in monocytes and prolonged relapse-free survival time in osteosarcoma patients with lung metastasis in a Phase II clinical study. GM-CSF therapy in patients with lymphoma, breast cancer, or neuroblastoma was shown to increase antibody-dependent cytotoxicity and endogenous TNF-a levels 111 , but produced no clinical response (regression of tumor) in Phase I and II studies 109 . In terms of adoptive cellular immunotherapy, although biological responses, including increases in cytokine levels, have been shown, clinical responses have been almost absent 112-114 .

Association Between TAM Density and Patient Prognosis

The association between TAM density (determined by average of macrophage counts under 400 x field microscopy) and tumor proliferation, angio-genesis, and the clinical course and outcome of human cancer has been investigated in a number of studies. A high TAM density has been reported to correlate with a high proliferation index of cancer cells in breast cancer, prostate cancer, and endometrial cancers 9-11 . TAM density was also reported to be associated with the differentiation of cancer cells and tumor size in a variety of human cancers, including breast cancer, bladder cancer, and glioma 12-14 . An association between macrophage infiltration and tumor-associated angiogenesis has also been demonstrated 14-20 . TAM density has been shown to correlate with tumor microvessel density (MVD) in a variety of human cancers, including endometrial, ovarian, breast, prostate, bladder, melanoma, and central nervous system malignancies 14-20 . Tsutsui et al. 21 showed that TAM density correlated...

Anti Hormone Action

By definition, all oestrogen targeted endocrine therapies have the common goal of depriving breast cancer cells of their required oestrogenic stimulation and reducing its productive cross-talk with interactive growth factor signalling elements to promote cell cycle arrest and induce cell loss. They achieve this either by lowering circulating oestrogen levels (using LH-RH analogues and aromatase inhibitors), or by antagonising their cellular actions by competition for ERs (using anti-oestrogenic drugs) (Nicholson and Johnston, 2005). Although such distortions of oestrogen mediated signalling have been described in terms of both genomic and non-genomic responses, characteristically, these actions are not simple and in some instances vary between procedures associated with oestrogen withdrawal from ERs and those which involve ER occupancy by anti-oestrogenic drugs. Because of this, the different modalities used to treat breast cancer patients will be dealt with separately.

ER Positive Disease

The retention of functional ERs in breast cancer models resistant to SERMs often allows a subsequent response to either fulvestrant or oestrogen withdrawal and most likely stems from the capacity of these treatments to lower nuclear and membrane ER signalling and their cross-talk with growth factor signalling elements. Unfortunately, such treatment responses are short-lived and the development of resistance involving altered growth factor signalling appears inevitable with all forms of endocrine therapy in experimental models. Improved responses, however, are often achieved with anti-growth factor therapies which can bring about growth inhibition lasting many months in vitro (Nicholson et al., 2007) and in vivo (Massarweh et al., 2008). To date success in this area has been achieved using inhibitors of growth 2006). As such, it is now perceived that drugs which target multiple growth factor receptors (e.g. lapatinib which targets EGFR and HER2), or common convergence points arising...


HSP27 is a protein particularly easily detectable and identifiable by pro-teomic approaches. This protein is reported to be differentially expressed in many pathological situations. In fact, differential proteomics allowed identification of HSP27 as a potential marker of neuroblastoma 112 , lymph node metastasis 113 , chemotherapy response in patients with esophageal adenocarcinoma 114 . More than 120 publications are retrieved by a PubMed search when proteomics is combined with HSP27. Many pathological situations may module HSP expression and secretion. Caution must therefore be exercised before using HSPs as diagnostic or prognostic markers of any given disease.


Interleukin-6 (IL-6) is a pleiotropic cytokine that is produced by fibroblasts, macrophages and lymphocytes. IL-6 is important in the regulation of local oestrogen biosynthesis in breast tissues by activating enzymes involved in oestrogen synthesis aromatase, oestradiol 17p-hydroxysteroid dehydrogenase and estrone sulfatase (Speirs et al. 1993 Duncan et al. 1994 Singh et al. 1995 Newman et al. 2000). In vitro, IL-6 can activate ERa in primary breast cancer cells (Speirs et al. 2000). Prostaglandin E2 (PGE2) can have similar stimulatory effects on oestrogen synthesis and also regulates IL-6 production in fibroblasts (Singh et al. 1999 Zhang et al. 1988). The significance of IL-6 in breast cancer is not clear (Kn pfer and PreiB 2007) probably due to its multiple variable effects. The in vitro data, its ability to regulate local oestrogen synthesis and its expression in stromal cells of breast cancers suggest that further studies to investigate whether it has a role in endocrine...


In addition to the encouraging results being produced from the clinical trials using 17-AAG as a single agent, evidence of activity with 17-AAG has also been reported in combination with trastuzumab in trastuzumab-refractory ERBB2-positive breast cancer (Modi et al., 2007), with the proteasome inhibitor bortezomib (Mimnaugh et al., 2004) which may offer a therapeutic strategy for the treatment of multiple myeloma, and with cytotoxics such as paclitaxel as an effective therapy in lung adenocarcinoma patients (Sawai et al., 2008). The combination of 17-AAG with cytotoxic agents such as paclitaxel, cisplatin and oxalipatin (Munster et al., 2001 Rakitina et al., 2003 Vasilevskaya et al., 2003 Vasilevskaya et al., 2004), tyrosine kinase inhibitors like imatinib (Radujkovic et al., 2005) and radiation treatment (Enmon et al., 2003 Bisht et al., 2003) have been studied with positive results being observed. In collaborative studies with Professor Ann Jackman and colleagues, we have...

Concluding Remarks

9 Volodko N, Reiner A, Rudas M, Jakesz R. Tumour-associated macrophages in breast cancer and their prognostic correlations. Breast 1998 7 99-105. 21 Tsutsui S, Yaduda K, Suzuki K, Tahara K, Higashi H, Era S. Macrophage infiltration and its prognostic implications in breast cancer The relationship with VEGF expression and microvessel density. Oncol Rep 2005 14 425-431. 33 Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 2000 6 3282-3289. 37 van-Netten JP, Ashmead BJ, Parker RL, Thornton IG, Fletcher C, Cavers D, et al. Macrophage-tumor cell associations A factor in metastasis of breast cancer J Leukoc Biol 1993 54 360-362. 40 Hildenbrand R, Wolf G, Bohme B, Bleyl U, Steinborn A. Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident...


The most likely mechanism of tamoxifen sensitisation by triciribine is inhibition of AKT activation. Consistent with this hypothesis, previous studies have shown that inhibition of the AKT activator, phosphoinositide-3 kinase (PI3K), can sensitise to endocrine therapies in in vitro and in vivo models and that activation of AKT causes resistance to tamoxifen in breast cancer models and tumours (Campbell et al. 2001 Clark et al. 2002 Perez-Tenorio et al. 2002 Sabnis et al. 2007).

Sources of Estrogens in Human Breast Tissue

17 -Estradiol is biologically the most active estrogen in breast tissue. Circulating estrogens are mainly originated from ovarian steroidogenesis in premenopausal women and peripheral aromatization of ovarian and adrenal androgens in postmenopausal women 8 . The importance of ovarian steroidoge-nesis in the genesis of breast cancer is highlighted by the fact that occurring naturally or induced early menopause prior to age 40 years significantly reduces the risk of developing breast cancer 8, 44-46 . However, the uptake of 17b-estradiol from the circulation does not appear to contribute significantly to the total content of estrogen in breast tumors, since the majority of estrogen present in the tumor tissues is derived from de novo biosynthesis 47-50 . In fact, the concentrations of 17 -estradiol in breast cancer tissues do not differ between premenopausal and postmenopausal women, even though plasma levels of 17 -estradiol decrease by 90 following menopause 51 . This phenomenon might...

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...

Historical Perspective

Humans have always attempted to improve their health by ingesting or administering drugs. Examples appear throughout written history, from every continent and culture. Noah produced alcohol 1 and Christ was offered a sedative to ease the pain of crucifixion 2 , The use of opium was described by Theophrastus in the third century b.c., the stimulating power of methyl-xanthines was exploited by ancient Arabian shepherds and priors, and the paralyzing properties of curare were recognized by native South Americans centuries before the arrival of Sir Walter Raleigh 3 , The chemotherapy of cancer, which many consider a modern development, has existed in some form for over 500 years 4 . Vaccination, the intentional exposure to pathogens, was used in China and India to prevent smallpox and other infections 5 centuries before the birth of either Jenner 6 or Pasteur 7 .

Minerals and vitamins

Seaweeds are rich sources of some important minerals and vitamins. In particular, seaweeds contain good amounts of iodine, calcium, and iron among others. Iodine content of seaweeds is incomparable with the highly consumed terrestrial vegetables as seaweeds are much better sources of iodine. However, amounts are varied with phylum, season, and environmental, geographical, and physiological variations. Brown algae have recognized as much important sources of iodine and have utilized extensively for the prevention and treatment of iodine deficiency goiter. Further, scientific reports link the potential of iodine in inhibiting tumorogenesis with the high amount of iodine in some seaweed species (Funahashi et al., 1999). In line with this capability of iodine in seaweeds, epidemiological studies suggest that high dietary seaweed content must have accounted for the low prevalence of breast cancer in some countries of Asia.

Membrane Transporters In Therapeutic Drug Responses

DRUG RESISTANCE Membrane transporters play critical roles in the development of resistance to anticancer drugs, antiviral agents, and anticonvulsants. P-glycoprotein, which exports many chemotherapeutics from cells, is overexpressed in tumor cells after exposure to cytotoxic anticancer agents. Other transporters (e.g., breast cancer resistance protein BCRP , organic anion transporters, and several nucleoside transporters) also have been implicated in resistance to anticancer drugs.

Summary and Future Perspectives

Prolonged exposure to estrogen has long been identified as a risk factor for human breast cancer, but the role of estrogen in the development of human breast cancer has been difficult to ascertain. One of the difficulties is to relate breast cancer development to circulating levels of estrogens. The levels of free estrogens are significantly higher in the primary breast cancer tissues than those in the circulation 47 , highlighting the importance of in situ metabolism of estrogens by estrone sulfatase and aromatase 66, 205 . There are two mechanisms that have been considered to be responsible for the carcinogenicity of estrogens a 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 139,140 . Since local synthesis of estrogen in the stromal...

Prevalence Of Chronic Pain

A patient with chronic pain may be anyone you see or know. They may be young or old, wealthy or homeless. Chronic pain does not respect age, race, financial status, or gender. It can affect anyone at any time, and the effects of the pain can be life changing. The pain can be the result of surgery, an injury, disease, or treatments such as chemotherapy, or it may just start for no apparent reason. Once the pain occurs, it will affect every aspect of the person's life. Every patient with chronic pain has a story to tell of how the pain has changed their lives and how they have learned to adapt and cope with it.

Characteristic Properties Of Cancers And Cancer Cells

As cancers progress, the numbers of alterations in their genome tend to increase. Therefore, cancers, even if outwardly homogeneous, usually consist of cell clones that differ at least slightly in their genetic constitution. The variant clones are continuously selected for those proliferating fastest, tolerating adverse conditions best, capable of evading immune responses, etc., with the best-adapted cell clone dominating growth (Figure 1.5). This variation becomes particularly evident during tumor treatment by chemotherapy which exerts a strong selection pressure for those cell clones carrying alterations that allow them to survive and continue to expand in spite of therapy.

ABC Transporters Abstinence

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters constitute a superfamily of primary active transport systems that are present from prokaryotes to humans. ABC transporters hydrolyze ATP to transport various substrates across cellular membranes. 48 ABC transporters are present in humans and are classified in seven subfamilies. The human ABCB1 or P-glycoprotein is responsible for multiple drug resistance (MDR) in pumping chemotherapeutic drugs out of the cell. A few ABCC members, also known as MRP (multiple drug resistance associated protein), and ABCG2 or BCRP (breast cancer resistance protein) are like, P-gp, expressed at the BBB where they play a protective role for the brain against xenobiotics.

Nanobiotechnology for the assembling of hemoglobin with other enzymes

Can more easily perfuse the abnormal microcirculation of tumors to supply oxygen needed for chemotherapy or radiation therapy. With a circulation half-time of 24 h, the effect can be adjusted to the duration of the chemotherapy or radiation therapy. When used together with chemotherapy, PolyHb decreases the growth of tumor and increases the lifespan in a rat model of gliosarcoma brain tumor (Pearce and Gawryl, 1998). We have recently crosslinked tyrosinase with hemoglobin to form a soluble PolyHb-tyrosinase complex (BL Yu and Chang, 2004) (Fig. 2.2). This has the dual function of supplying the needed oxygen and at the same time lowering the systemic levels of tyrosine needed for the growth of melanoma. Intravenous injections delayed the growth of the melanoma without causing adverse effects in the treated animals (BL Yu and Chang, 2004).

Targets For The Medicinal Chemist 131 Hormones as Targets

The interaction of a cell-signalling substance with a receptor can initiate a further series of enzyme-catalysed events within the cell. These enzymes may be the target for drugs. The nucleic acids form further targets particularly in cancer chemotherapy. Interferance with the biosynthesis of nucleic acids, their translation and replication, each form targets for drugs. Thus there are a plethora of potential targets for drug action. A crucial stage in the combat of a disease is the selection of an appropriate target. The selection of the target determines the bio-assay for a drug.

Drug Administration and Drug Effectiveness

Perhaps for this reason, the modern practice of healing usually involves medicine, an agent or elixir given as treatment.1 The new millennium finds us rich in the knowledge of agents advanced in the art of harvesting or synthesizing remedies steadfast in the belief that cancer, heart disease, and neurodegeneration will eventually yield to these potions. Our skill in making medicine is far-reaching. Today, it would be difficult to find the person who has not personally experienced the healing force of antibiotics, vaccines, or modern chemotherapy. Unfortunately, it would be equally difficult to find the person who has not endured the premature death of a friend or relative due to unbeatable infection or cancer. So we continue to search for better therapeutics.

Drug Targeting In The Absence Of Specific Targeting Moieties

Thus far, the EPR effect has been credited for the clinical development of SMANCS 11 and the pHPMA-doxorubicin conjugate (PK1) 4 For example, arterially administered SMANCS in patients with primary hepatoma displayed tumor blood ratios as great as 2000 when combined with Lipidol as carrier 11. Furthermore, the clinical trials of PK1 suggested that this drug displayed antitumour activity in chemotherapy-refractory patients, considerably reduced toxicity compared with doxorubicin, and provided evidence of tumor-selective targeting 4.

The Experience Of Visceral Pain

Visceral pains may also occur secondary to iatrogenic damage of the viscera and their associated nerves produced by interventional therapies, surgery, chemotherapy, and or radiation. There is a poor correlation between the amount of visceral pathology and the intensity of associated pain. For example, very extensive processes with ongoing tissue damage (e.g. ulcerative colitis or gastric perforation) may produce little or no pain in some individuals, while minimally discernable pathology may produce out-of-control pain in others.

Inherited Predisposition To Cancer

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 increased risk in cancer families with an autosomal-dominant mode of inheritance is caused by an inherited mutation in a single gene. The affected genes are usually tumor suppressor genes ( 5) and more...

Materials and Methods

Rats inoculated with allogeneic hepatoma cells (KDH-8) were randomly divided into three groups rats in group I (n 7) were untreated and served as the control, rats in group II (n 7) received a single dose of 2', 2'-difluoro-2'-deoxycytidine (gemcitabine, 90 mg kg, i.v.), rats in group III (n 8) received cyclophosphamide (150 mg kg, i.p.). Dual-tracer tissue distribution studies using 18F-FDG and 99mTc-annexin A5 were performed 48 h after the chemotherapy. Briefly, 99mTc-annexin A5 was first injected and 5 h later 18F-FDG was injected. Six hours after the 99mTc-annexin A5 injection (1 h after 18F-FDG), the rats were killed and the organs, including the tumor tissues, were excised to determine the radioactivities of 18F-FDG and 99mTc-annexin A5 ( ID g per kg).

G3139 in Melanoma Clinical and Preclinical Results

However, a somewhat different set of conclusions was drawn by Gekeler et al.,23 although these authors did not perform experiments in melanoma cells. Prior to this work, it had been believed that in animals devoid of T cells, human tumor xenograft responses to CpG ONs required cytotoxic chemotherapy.24,25 However, treatment of nude mice bearing the H69 SCLC xenograft with G3139 produced tumor growth arrest, which was similar in scale to the effects of cisplatin, and to H1826, an optimized immune stimulatory oligo.26 A G3139 derivative in which all the deoxycytidine residues were C5-methylated did not produce any inhibition of tumor growth in this model, although its ability to downregulate Bcl-2 expression in vitro was essentially equivalent to that of G3139 itself. The A2780 ovarian carcinoma and the 549 lung adenocarcinoma xenograft models essentially behaved similarly. It was this lack of activity after cytosine C5-methylation that convinced Gekeler et al.23 that immunostimulation...

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.

Results and Discussion

Figure 3 shows the uptake levels of 99mTc-annexin A5 and 18F-FDG in the tumor after a single dose of chemotherapy using gemcitabine or cyclophosphamide. The uptake levels of 99mTc-annexin A5 in the tumor were significantly increased by the Fig. 3A,B. Uptake levels of A 99mTc-hydrazinomcotinamide (HYNIC)-annexin A5 and B 18F-FDG in the tumor after a single dose of chemotherapy using gemcitabine or cyclophosphamide. Group I, untreated control group II, gemcitabine (90 mg kg, i.v.) group III, cyclophosphamide (150 mg kg, i.p.). *P < 0.01 vs control. ID g kg, percentage of injected dose per gram X kg chemotherapy (0.031 0.005 ID g per kg in group I (control), 0.062 0.012 ID g per kg in group II (gemcitabine), 0.050 0.012 ID g per kg in group III (cyclophosphamide) P < 0.01). On the other hand, the uptake levels of 18F-FDG in the tumor were significantly decreased by the chemotherapy (0.743 0.084 ID g per kg in group I, 0.483 0.118 ID g per kg in group II, 0.583 0.142 ID g per kg in...

MiR372 and miRNA373 Regulate LATS2 Expression

Our results thus far indicate that miR-371-3 cluster suppresses an inhibitor of CDK activity and that this function is important for the development of TGCTs. To start to identify relevant targets of miR-372& 3, we took advantage of the fact that miRNAs may cause limited destruction of their target mRNAs apart from inhibiting their translation (Lim et al., 2005). We performed an mRNA-expression array analysis comparing RASV12-expressing BJ ET cells either containing p53kd or expressing the miR-371-3 cluster (Figures 5A and S9). We chose this setup as both cell types proliferate in the presence of oncogenic stress, thus canceling out the profound effects of cells going into senescence. We first looked in the p53kd cells and found p53 itself and many of its transcriptional targets to be downregulated compared to the cluster-expressing cells (Figure 5A). This independently confirms our previous results (Figure 4A) indicating that miR-372& 373 do not directly inhibit p53 activity....

Clinical Trials in Advanced Melanoma

The data obtained from this relatively small Phase I II trial, which was itself based in part on the pre-clinical 518A2 human tumor xenograft melanoma model (as described above), led to the initiation of the largest Phase III trial in advanced melanoma ever, sponsored by Genta, Inc. (Berkeley Heights, NJ). Between July 2000 and February 2003, 771 chemotherapy-naive patients with advanced malignant melanoma were randomly assigned to receive treatment with dacarbazine alone (1000 mgm-2 day-1 i.v. for 60 minutes) or oblimersen sodium (7mgkg-1 day-1 by continuous infusion for five days) followed by the same dacarbazine dose.53 Figure 2.7 Depicted are Kaplan-Meier survival curves analyzed by LDH decile in melanoma patients receiving chemotherapy unrelated to oblimersen as part of EORTC 18951 (unpublished data courtesy of L. Itri, Genta Inc., Berkeley Hills, NJ). Figure 2.7 Depicted are Kaplan-Meier survival curves analyzed by LDH decile in melanoma patients receiving chemotherapy unrelated...

Natural Occurrence of Oleamide

First to quantitatively report on oleamide levels in rat plasma (10 ng mL) and cerebral spinal fluid (44 ng mL) (Hanus et al., 1999). Oleamide has also been reported to be present in three human breast cancer lines (Bisogno et al., 1998) and in human tear film, although there is disagreement over the relative contribution of oleamide to the total content of nonpolar lipids in this secretion (Butovich et al., 2007 Nichols et al., 2007). Reports on the natural occurrence of oleamide must be considered with caution, due to its widespread use as a slip agent in the production of polyethylene products commonly used in laboratory research. This complication is avoided with a biosynthetic labeling approach using either radioactive or stable mass isotopes. Biosynthetic labeling has been used to demonstrate the biosynthesis of oleamide by different cell types. Initial studies were carried out in the mouse neuroblastoma N18TG2 cell line (Bisogno et al., 1997 Merkler et al., 2004). As will be...

Role of miR3723 in TGCT Development

Our results suggest that during transformation, the activities of miR-372& 3 circumvented the need to mutate p53, leading to a DNA-damage-sensitive transformed phenotype. These characteristics of miR-372& 3-transformed primary human cells therefore suggest a role in wt p53-tumor genotypes that are also sensitive to chemotherapies, including irradiation. Indeed, TGCTs conform to this profile (Masters and Koberle, 2003). This could for instance be a result of high mdm2 levels, as was previously suggested for mouse teratocarcinomas (Lutzker and Levine, 1996). However, by several criteria mouse teratocarci-nomas are counterparts of human germ cell tumors of neonates and infants rather than TGCT (Oosterhuis and Looijenga, 2005). Indeed, while the first show high mdm2 expression levels, this was not demonstrated in TGCT (Mostert et al., 2000). Therefore, it is highly significant that we found that miR-372& 3-expressing TGCTs did not contain mutated p53 alleles, whereas a subset of...

Integrating Different Approaches

Thus, the use of complementary approaches including heritability analysis, linkage analysis, expression studies, and association studies can be used to identify and characterize novel genes important in sensitivity and resistance to chemotherapy. Ultimately, one must consider validating the genes identified in an appropriate cell or tissue (Fig. 3). Among the advantages of using linkage analysis and association in cell-based models to identify genetic variants important in sensitivity to drugs are (1) The use of cell lines from pedigrees allows genetic strategies such as linkage analysis to be used to identify regions of the genome important in sensitivity to chemotherapy without any assumptions about the nature of the genes likely to be involved (2) if heritability is low or linkage does not result in high lod scores, global association and expression studies can be performed on the CEPH and Yoruban HapMap samples (3) chemotherapy does not have to be given to non-affected family...

General Considerations

On the other hand, there may be other reasons for the observed trends. As the changes have occurred over one or two generations, it is possible that the changing environment (including changes in lifestyle) may be at least partly responsible. A number of possible factors that might affect sperm production have been suggested, including dietary deficiency of selenium (a vital component of selenoenzymes which have a number of roles including the maintenance of normal sperm motility, testicular morphology and testosterone metabolism). Intakes of selenium are reported to be falling in Britain and Europe.46 Different types of underwear have also been reported to affect the production of sperm brought about by, for example, temperature changes caused by an increased tightness of fit.47 The epidemiological observations, in particular the apparent upward trends in testis, prostate and breast cancer incidences, are of concern and should be followed closely whether or not chemical endocrine...

Exceptions To The Rules

Cisplatin (Fig. 2.6) is a cancer chemotherapy drug. With only 11 atoms, it is smaller and less complex than most drugs. As implied by the discussions of specificity earlier in this chapter, one might expect this to result in unwanted side effects. Indeed, cisplatin use often causes severe nausea, hair loss, weight loss (perhaps indirectly from the nausea), kidney damage, hearing loss, sometimes some nerve damage, and electrolyte disturbances. However, cisplatin was originally the only hope to extend the life of patients with many forms of cancer. Thus, the severe side effects were acceptable. Today, cisplatin is still used for some forms of cancer, often in small doses mixed with other drugs having less severe side effects. Figure 2.6 The cancer chemotherapy drug cisplatin.

Estrogens And Their Involvement In Carcinogenesis

The link between ovarian function and breast cancer has been known for more than a century, and endocrine therapy can be considered as the oldest, safest, and best-established systemic treatment for breast cancer. Many breast and endome-trial tumors are estrogen-dependent, and for this reason their treatment is based on the modulation of these hormones. This can be achieved directly by

Enzymes Transporters Receptors and Other Protein Targets

GeneCards (http index.shtml) is another valuable resource on human genes. Genetic polymorphisms of drug-metabolizing enzymes can result in individual differences in pharmacokinetics and there is a growing appreciation that genetic polymorphisms of drug transporters can also exert a significant effect on pharmacodynamics. A wide variety of transporters capable of drug efflux and drug uptake have been identified. Efflux transporters are mainly represented by the ABC cassette (ABC) family that utilizes energy derived from the hydrolysis of ATP to move substrates out of cells. Efflux transporters include the multidrug resistance proteins (MDR), the multidrug resistance-related protein (MRP), the bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). Uptake transporters, on the other hand, facilitate the translocation of drugs into cells by exchange or cotransport of in-tracellular and or extracellular ions (Na+, H+, HCO-). Members of this...

Nonsteroidal antiestrogens SERMs

The first discovered antiestrogen was clomiphene, but its development for the treatment for advanced breast cancer was discontinued because of concerns about potential side effects. In 1974, tamoxifen was the first antiestrogen to be approved for the treatment of advanced breast cancer (Great Britain) and in 1977 a similar approval was given by the FDA. Since then, tamoxifen has become the standard therapy for all types of ER-positive breast cancer. In the 1990s, it was also the first cancer chemopreventive agent approved by the FDA for the reduction of breast cancer in pre- and postmenopausal women with high risk.5 Tamoxifen also binds with high affinity to other targets, such as the microsomal antiestrogen

From genomics to proteomics

The SSH (suppression subtractive hybridisation) technique, for example, has helped to identify new genes of interest, an important step before the identification of novel therapeutic targets. In this technique cDNA is generated from mRNA extracted from two types of tissues or cells, one tissue being collected from affected patients, and the other from healthy controls. For example, a group analysed genes induced by BRCA1 (an already known vulnerability gene in breast cancer) in order to find other potentially involved genes. The study thus compared control breast carcinoma cells (driver) with cells ectopically expressing BRCA1 (tester), and found that a new set of 30 genes might be involved in the risk of breast cancer (Atalay et al. 2002).

Clinical applications

The majority of clinical experience using diphtheria-based fusion protein toxin constructs has been with the IL-2 receptor targeting constructs. The specific expression of the high affinity IL-2 receptor on only activated and proliferating T cells makes DAB389IL-2 a potential therapeutic for the treatment of both T-cell mediated malignancies and autoimmune diseases. The progression of disease in both states often results in the emergence of resistance to chemotherapy and subsequent treatment failure, and highlights the need for the development of new therapeutic agents.

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