A Natural Skin Cancer Cure

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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How I Survived Malignant Melanom

By The Time You've Finished Reading How I Survived Melanoma Skin Cancer Seven Survivors Tell Their Stories. You'll Feel Like A New Person, with A New, More Positive Outlook! You will learn: 1. How do I know if I have melanoma? What are the signs and symptoms? I wanted to know why the doctor was so concerned when she looked at that little mole on my forearm. What was it that looked so sinister? How worried should I be? Was the doctor over-reacting? 2. What tests will the doctor carry out to see if I have melanoma? Will they be able to tell me on the spot if there is a problem? Or will I have to wait for days, fretting about whats going on? 3. How curable is melanoma? If they do tell me its melanoma, what exactly does that mean? Is it a death sentence? Will they tell me You have 12 months to live. Get your life in order and prepare for the worst.? 4. What are the stages of the disease? The reading Id done said that there were different stages of melanoma. What are the symptoms of each stage? What are the survival rates of each stage? If I had a later stage melanoma, wouldnt I know about it? Wouldnt I actually feel like I was sick? 5. How quickly does the disease progress or spread? Should I have gone to the doctor sooner? Id noticed the mole changing over about 3 months. Was this delay critical? 6. How is melanoma normally treated? Would I have to go through chemotherapy and radiation treatment? If so, for how long? What are the odds of curing the disease using these treatments? How extensive is any surgery likely to be? How big will the scars be? 7. What are the common side effects of the treatments? Would I lose my hair? Would I become sterile? What else could I expect? 8. What alternative treatments are available? Id heard of people going on special macro-biotic diets. Id seen lots of herbal remedies on the internet. Which of these are proven and documented, and which ones are snake oil? Is it possible to combine alternative treatments with surgical other western treatments? How do I find a doctor that is open to using both alternative and western treatments? 9. What are the latest treatments being developed, and who is carrying out clinical trials of these new treatments?

How I Survived Malignant Melanom Summary

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The Role of Bcl2 in Melanoma

How are we to understand the role of Bcl-2 in melanoma The general question of the relevance of Bcl-2 expression to cell death has been discussed by Blagosklonny,30 who notes that it is not a direct one. He states that it would be expected that cells which express Bcl-2 would be apoptosis resistant, and vice versa, yet Bcl-2 appears to be unnecessary for many cell types. Furthermore, Bcl-2 is often expressed at low levels in highly apoptosis-resistant cells, and its expression in colorectal, breast and lung carcinomas is associated with 'increased apoptotic index, lower risk of distant metastases, and improved prognosis'. In addition, cell lines ' . . . become resistant due to a strong selection during establishment of cells in culture, over-expression of Bcl-2 simply cannot further increase resistance and the effects of Bcl-2 are undetectable'. Tumor cells may also downregulate proteins involved in the apoptotic cascade. An example in melanoma is Apaf-1, which is downstream of Bcl-2,...

G3139 Causes Bcl2 Independent Apoptosis in Melanoma Cells

Older work in a SCID-hu melanoma model had hinted that the effects of phos-phorothioate ONs were non-specific. Subsequently, a much more detailed study of the effects of G3139 treatment of melanoma cells was conducted by Lai et a .41 The viability of 518A2 melanoma cells, when treated with concentrations of G3139 as high as 40 mM in the absence of a lipidic delivery agent, was not affected. In contrast, treatment with 100 nM G3139 in complex with Lipofectamine 2000 caused extensive apoptosis, as measured by cell-surface Apoptosis of the 518A2 melanoma cells led to cleavage of PARP-1, cleavage of pro-caspase-3 to caspase-3 (and increased DEVDase activity) and the cleavage of Bid to tBid, although no activation of pro-caspase-8 was observed. These changes were initiated as early as 9.5 hours after initiation of the G3139 trans-fection, at a time when neither Bcl-2 protein expression nor DCm were decreased (Figure 2.1). Similar events were observed in the 346.1, 201.2, 333.1 and A375...

Clinical Trials in Advanced Melanoma

A small Phase I II trial of G3139 (brand name oblimersen) in combination with dacarbazine in advanced melanoma was published by Jansen et al.52 Dacar-bazine is apparently the most active single agent in this disease, although its response rate is approximately 7 . It was approved by the Food and Drug Agency (FDA) in 1975, which marked the last time that the agency has approved any agent for this indication. Oblimersen was administered via continuous infusion for 14 days. The initial dose was 0.6 mg kg-1 day-1, which was rapidly increased in subsequent patients in the absence of toxicity, with a dose maximum of 6.5 mg kg-1 day-1. Dacarbazine was administered separately at a dose of 200 mgm-2 on days 5-9. Treatment cycles were repeated monthly. Levels of Bcl-2 protein expression were evaluated in biopsy specimens, but the maximum decrease in Bcl-2 expression was highly variable, and the numbers of samples were far too few for any statistically meaningful conclusions to be drawn. Small...

PolyHbTyrosinase Artificial Cells for Melanoma Introduction

Melanoma, a fatal skin cancer, is a common tumor which accounts for 10 of all malignancies. The incidence of melanoma has risen dramatically in the last century, doubling every 10 years in many countries. The incidence is now approximately 10 per 100,000 per annum in Europe, giving an approximate lifetime risk of 1 in 200 (Katsambas, Nicolaidou, 1996). Melanoma is most commonly found on the skin, with 10 in the eyes. At least 20 of people diagnosed with melanoma progress to advanced disease and die within five years of diagnosis (Borden, 2002). At present, despite the use of adjuvant therapy, chemotherapy, immunotherapy and radiation therapy, the median survival of patients with metastatic melanoma is about six months. Tyrosine is important in the metabolic cycle of melanoma and malignant melanomas require higher concentrations of tyrosine than other cells for growth. Research, especially those from Meadows' group, has shown from in animal studies, that lowering of systemic tyrosine...

Polyhemoglobintyrosinase for melanoma

PolyHb-tyrosinase carries out two functions 1) Tyrosinase can remove tyrosine needed for growth by melanoma. With a molar Fig. 7.7. (A) Melanoma needs a higher concentration of tyrosine for growth. Similar to PolyHb-asparaginase, crosslinking of an excess of hemoglobin to tyrosinase also stabilizes and separates the tyrosinase from the external large molecules, while allowing tyrosine to enter for conversion. Our study shows that intravenous injection of PolyHb-tyrosinase retards the growth of melanoma in a mice model (Yu and Chang, 2004a). We inoculated B16F10 cells subcutaneously into mice and when the tumor volume reaches an average of 125 mm3 on day 9, 2. Remove tyrosine needed by melanoma Fig. 7.7. (B) PolyHb-tyrosinase being a soluble macromolecule of nanodimension, it can better perfuse the imperfect vasculature of tumor to supply oxygen needed for chemotherapy and radiation therapy. At the same time, the tyrosinase component can remove tyrosine needed by melanoma for growth....

G3139 in Melanoma Clinical and Preclinical Results

In earlier studies, treatment of 518A2 melanoma cells in vitro with G3139 complexed with Lipofectin led to as much as a 60 downregulation of Bcl-2 protein expression (200 nM, 48 h).21 518A2 cells were then xenografted into SCID mice, and treated with G3139 for 14 days at 5mgkg-1 day-1 via Alzet minipumps. Dacarbazine, the most active drug in clinical melanoma, was injected at 80mgkg_1 intraperitoneally (i.p.) from days 12 to 16. Apoptosis, as assessed by terminal uridine deoxynucleotidyl transferase nick end labeling (TUNEL) assay, increased from 0.7 in the control, saline or mismatched ON group to 3.3 in the antisense group. Levels of Bcl-2 protein expression were stated as being reduced by 66-72 in the G3139-treated group, but only a single Western blot example was shown. Furthermore, the reverse control oligo altered the flanking sequences of the CpG motifs relative to G3139, while the mismatched oligo eliminated them entirely. The authors of this work were aware of these problems,...

Melanoma

The third most frequent cancer of the skin, melanoma, is derived from melanocytes. These cells belong to a distinct cell lineage as keratinocytes. During development, melanocyte precursors migrate from the neural crest to the basal layer of the skin. Melanocytes specialize in synthesizing the pigment melanin from tyrosine. The enzymes of melanin biosynthesis, such as tyrosinase, are only expressed in this cell type. The insoluble pigment is transported by dendritic processes to surrounding epidermal keratinocytes and deposited in them. Differentiating keratinocytes transport melanin to the upper layers of the skin where it absorbs visible and UV light, protecting the living cells of the skin. The differences in pigmentation and its inducibility are categorized as 'skin types' by dermatologists. For instance, persons with skin type I have low pigmentation and very little inducibility, whereas persons with skin type II have also relatively pale skins, but develop some pigmentation in...

Historical Milestones

2004 Yu & Chang (Melanoma Res J) 2006 Liu & Chang (J Liver Trans) Nanobiotechnological approach of PolyHb-tyrosinase delays the growth of melanoma in a rat model AC encapsulated bone marrow stem cells regenerate liver resulting in recovery and survival of rats with 90 of liver surgically removed

Characteristic Properties Of Cancers And Cancer Cells

Altered differentiation Many cancers consist of cells which resemble precursor cells of their tissue of origin and have not embarked on the normal course of differentiation, whereas others show properties of cells at intermediate stages of differentiation. Some cancers, however, do consist of cells with markers of full differentiation, with the crucial difference that they continue to proliferate. In these cancers, it is not difficult to identify the cell of origin, which is important for diagnosis. Many cancers, however, express markers that do not occur in their tissue of origin ( 12.5). Frequently, cancer cells express proteins which are otherwise only found in fetal cells. Such proteins, e.g. carcinoembryonic antigen in colon carcinoma or alpha-fetoprotein in liver cancer are called 'oncofetal' markers. Other proteins expressed in cancers are never synthesized in the original cell type, e.g. 'cancer testis antigens' in melanoma and various peptide hormones in small cell lung...

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).

Pokeweed antiviral protein and saporin

One group has reported a recombinant basic fibroblast growth factor-saporin fusion protein which was purified in good yields and showed anti-melanoma activity in a mouse model (Lappi et al., 1994). Interestingly, intracellular proteolysis appeared necessary to release active saporin in the cytosol. Resistance phenotypes for either PAP or saporin chimeric protein treated cells has not been reported.

Depressants Promazines Hydantoins and Barbiturates

The basis for synthesizing boronated promazines arose from localization studies of chloropromazines (CPZ) in melanoma-bearing cells.72,19c The first such boron-containing compounds were those in which the boron moieties were attached to the aliphatic nitrogen of CPZ.73 Unfortunately, the results with these compounds were not promising. After these initial syntheses, carborane-containing promazines were described in which the boron entity was incorporated into the aromatic rings of the phenothiazine nucleus. Figure 2.32 shows some of the examples of these compounds.

O Enzymes Blood Clotting Factors

Recombinant tPA (rtPA), alteplase (Activase), is identical with endogenous tPA. rtPA lacks a glycosyl residue at Asn184. At one time, rtPA was produced in two-chain form in CHO cultures. Now, large-scale cultures of recombinant human melanoma cells in fermenters are used to produce a product that is about 80 single-chain rtPA.

Apparent Diffusion Coefficient MRI

The concept of using ADC-MRI to evaluate the effects of therapy in solid tumors is based on the general observation of an increase in tumor ADC after cytotoxic treatments in several tumor types 161-163 . Lyng et al. 163 demonstrated in four different melanoma xenograft models that tumor ADC is inversely proportional to viable tissue cell density. It is thought that an increase in tumor ADC upon treatment reflects the development of necrosis through increased cell membrane permeability and extracellular fraction, and decreased cellularity which ultimately results in greater water mobility . 164 . In some tumor types such as intracranial gliomas, an early transient decrease in ADC has also been observed prior to subsequent ADC elevation, which may be due to treatment-induced cellular swelling 152,165 . These changes generally precede gross tumor regression, so that changes in tumor ADC appear to predict such regression.

Tumor Necrosis Factor a Potency Efficacy Noncorrelation

Noncorrelation was also observed by Teng et al., who demonstrated that TNF-producing and TNF-nonproducing tumor cells grow at similar rates in vitro but form different-sized tumors in vivo (116). The authors proposed several explanations for this lack of correlation, including the possibility that tumor cells when grown in vivo, rather than in vitro, were directly susceptible to the secreted TNF or that secondary mediators induced by TNF had an effect on the tumor cells (116). Alternatively, the mechanism of inhibition could be indirect and related to TNF effects on the blood vessels or other nonmalignant stromal components, including inflammatory cells that may be activated by TNF to destroy the tumor (116). Earlier work by Bromberg et al. addressed the discrepancy between the in vivo and in vitro activities of anti-TNF antiserum by proposing the following three possibilities (i) TNF is important for in vivo cellular communication, but different arrays of cells and cytokines...

The Role Of miRNAs In Cancer Diagnosis And Drug Discovery

Alterations in the gene copy number of miRNAs are detected in a variety of human cancers (41,42,43). Zhang et al. (41) showed that miRNAs exhibited high-frequency ge-nomic alterations in human ovarian, breast cancer, and melanoma using high-resolution array-based comparative genomic hybridization.

Dose versus Treatment Chronicity

Subcutaneous injection of cytokines is generally considered to be a benign route. However, the intraventricular route for the treatment of leptomeningeal metastases (LMD) has proved to be particularly toxic. In one study, 78 of patients developed a wakeful vegetative state after receiving intraventricular IFN-a at a wide range of doses (cumulative dose of 15 to 54MIU) (Meyers, Obbens, Scheibel, & Moser, 1991). It took an average of 3 weeks off of therapy for the patients to recover to their baseline performance status. The toxicity of intraventricular IL-2 for leptomeningeal melanoma appears to be more sporadic, with some individuals tolerating treatment without mood or cognitive side effects, and others developing severe reactions including delirium, obtundation, and death (unpublished data). Delayed effects are also problematic. Intraventricular IL-2 has been reported to cause a progressive dementia in a patient who appeared to be otherwise cured of LMD (Meyers & Yung, 1993).

In vitro cytotoxicity

Studies using various antibodies coupled to RTA have shown that Ag density correlates with the cytotoxic potency of the IT. This was approached by Casellas et al. (1982) using an RTA-IT directed against the melanoma-associated Ag p97. They found that melanoma cell lines expressing over 78,000 p97 Ag cell were efficiently killed by the IT whereas those expressing fewer than 5000 sites cell were not killed. However, the authors found no correlation between the cytotoxic potency of the IT and Ag density in those instances where the number of p97 Ag cell was above 78,000. By comparing the sensitivity of four sublines of CEM T-cell leukemia cells with different amounts of CD5 Ag to a T101 (anti CD5)-RTA IT, Laurent et al. (1986) found that the cytotoxic potency of the IT and the rate at which protein synthesis was inhibited correlated with Ag density in three of four cell lines. However, a fourth cell line having an intermediate CD Ag expression did not fall into this...

Steric Block Biological Activities of PeptidePNA Conjugates

Galanin-receptor mRNA, conjugated to a truncated Transportan version TP10.74 PNA-peptide conjugates have also been used to inhibit telomerase activity, by binding to the RNA component of the enzyme complex. For example, a 13-mer PNA disulfide-linked to Penetratin was able to inhibit tel-omerase activity in JR8 melanoma cells when incubated for 144 hours (IC50 7 mM).75 PNAs stably linked to short hydrophobic peptides rich in Leu and Phe have shown increased cell internalization and activity in vitro.76 Stimulated macrophages incubated with anti-inducible nitric oxide synthase (iNOS) PNA-peptide showed up to 44 decrease in nitric oxide synthase activity compared to non-targeted controls.

Contribution of caffeine to the anticarcinogenic activity of green tea

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

In vivo problems associated with RTAIT treatment

Hertler et al. (1987) measured serial anti-RTA and anti-murine immunoglobulin (anti-MIG) titers in 22 patients who received the anti-melanoma Immunotoxin XomaZymeR-Mel. Significant titers of anti-RTA and or anti-MIG were detected in 17 of 21 evaluable patients. Of the four patients not developing antibodies, two were likely immunosuppressed secondary to dexamethasone, and CCNU + dexamethasone respectively. Both patients who received ITs at a time when they had detectable anti-Immunotoxin antibodies experienced infusion reactions consistent with immune mediated allergic responses. In a further study using XomaZymeR-Mel (Mischak et al., 1990) human antibody responses to ITs components were evaluated in 21 melanoma patients. Twenty of the 21 melanoma patients produced antibodies against RTA, while 15 of 21 produced antibodies reactive with the murine monoclonal antibody component. Both IgM and IgG antibody responses were produced. Immunoglobulin responses were usually detected 1-2 weeks...

Potential tumor markers

Malignant melanocytes present defective melanosomes and tend to exhibit up-regulated melanogenesis. Melanogenuria (in the form of dark urine) is observed in some patients with widespread disease. End-product pigments, enzymes and melanin precursors or intermediates of the melanogenesis have therefore been measured in urine and blood from melanoma patients for more than 30 years. quantification of specific mRNAs, mostly in blood (plasma or serum). Tyrosinase appears to be the most reliable mRNA target for RT-PCR it is a specific marker of melanocytic differentiation, expressed both in primary and metastatic melanoma. Many researchers aiming at the detection of melanoma cells in blood, bone marrow, lymph nodes and sentinel nodes have pursued this promising line of investigation. Unexpectedly, the results are so far extremely variable and sometimes negative in advanced melanoma patients. Other evaluated serological markers from the melanogenesis pathway include the phaeomelanin...

Blood plasma or serum analysis

Using a radioenzymatic technique, Faraj et al.11 measured plasma l-DOPA in 98 melanoma patients. For those without metastases, the mean l-DOPA plasma concentration (1.01 0.12 mgL-1, n 21) was not different from that of normal controls (n 32). However, it was increased (p < 0.001) in patients with metastases to regional lymph nodes (2.08 0.46 mg L_1, n 65) and more distant metastases (8.40 3.50 mg L_1, n 12). The development from regional to distant metastases in four patients was accompanied by a 4-6-fold increase in the concentration of plasma l-DOPA. This clinical study, for the first time, suggested that measurement of l-DOPA in plasma might be useful in melanoma patients, at least in those with metastatic disease. Measuring l-DOPA by the technique of Faraj et al.11 was, however, cumbersome it should be enzymatically converted to dopamine and further to 3-O- 3H methyldopamine, before being extracted and characterized by radiochromatography.

Other Evidence For The Neuroprotective Effects Of Mao Inhibitors

Serum, and thereby growth factor, deprivation can induce PCD in a variety of different types of cells and is often considered a model for the death of vertebrate neurons during embryonic development. Serum deprivation of cultured melanoma cells leads to a high level of cell death within 24-48 h (48). Death can be blocked by both high doses of pargyline (1 mM) and lower doses of clorgyline, whereas deprenyl is completely ineffective at any concentration. Both high doses of pargyline and clorgyline also significantly reduced mitochondrial damage brought about by serum deprivation whereas deprenyl did not. Thus, these data provide another demonstration of protection from PCD by MAO-A inhibition that correlates with the maintenance of mitochondrial function.

In Vivo Efficacy Evaluations

The MTD and tumour growth delay (TGD) in Lewis lung cancer (LL 2) 13 and B16 melanoma syngeneic tumours in female C57BL 6 mice19 after a single IP injection were used to evaluate the biological consistency of CT-2103. In these studies the paclitaxel-equivalent MTD varied between 160 and 240 mg kg, and the mean SD range for TGD to 500 mm3 was 3.8 1.8 range 0.4 - 9.8 days for Lewis lung tumours and 6.2 3.2 range 1.3 - 13.2 for B16 tumors13,19. The TGD to 500 mm3 for paclitaxel in Cremophor-ethanol at its MTD of 80 mg kg was 2.0 + -0.9 range 0.4-3.5 days (n 16) in mice bearing the LL 2 and 2.0 + - 1.1 range 0.7-4.3 days (n 10) in B-16 model (p< 0.01 compared to CT-2103 for both models).

Antiproliferativeantitumoranticancer activity

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

Copper Imidazole Derivatives Complexes

The strong anti-tumour activity of the trans-bis (acetato) bis (imidazole) copper(II) complex Cu(O2CMe)2(HIm)2 , against the mouse cancer cell line B16 melanoma is well known.51 A similar complex Cu(O2CMe)2L2 (1), where L 1-methyl-4,5-diphenylimidazole, has been synthesized and its effects on the The chemotherapeutic potential (IC50) of 1, 3 and 4 towards the human squamous carcinoma tongue cell line, CAL-27, and the malignant melanoma (melanocyte) skin cell line, SK-MEL-31, was determined. TBZH was capable of killing both cancer lines only at higher concentrations with IC50 value of 91.7 and 136.9 mg ml, for the tongue and skin cell line, respectively. In the case of compounds 3 and 4, the IC50 values were almost identical (33.1 and 31.9 mg ml, respectively) in the CAL-27 cell line and 39.1 and 30.7 mg ml, respectively, in the SK-MEL-31 cell line. These doses were found to be significantly lower than that for the metal-free TBZH.

Clot lysis in vitro static model

In a static model of in vitro clot lysis, reteplase exhibited a lower thrombolytic potency than rt-PA and melanoma t-PA (13). In an assay in which human platelet-poor plasma (PPP), platelet-rich plasma (PRP) and whole blood clots were incubated in human citrate plasma, reteplase required a 6.4-fold higher molar concentration than rt-PA to achieve 50 lysis of PPP clot at 4 hours (13). Despite the lower potency, reteplase showed the same maximal efficacy as rt-PA in lysing PPP clots, but was less effective in the

Oral enzyme artificial cells to deplete other amino acids

These include the removal of tyrosine in tyrosinemia, histidine in histidinemia, and others. In addition, the basic results obtained here can be useful for analyzing the feasibility for use in other conditions. One example is the use of oral administration of artificial cells containing asparaginase to lower asparagine in leukemia. Asparaginase is used as an adjunct treatment in chemotherapy, but it has side effects when injected intravenously on a repeated basis. Oral use of asparaginase artificial cells if effective, would avoid the adverse effects related to intravenous injection. Removal of glutamine is another example. The use of oral tyrosinase artificial cells can effectively lower the systemic tyrosinase level. As described in the next chapter, we are studying this for potential application in melanoma, a skin cancer that depends on tyrosine for growth.

Brain To Body Central Nervous System Effects On The Immune System

Although the relationship between stress and immunity is quite complex, more acute and or mild stressors, in general, tend to be associated with activation of immune responses, whereas more chronic and intense stressors tend to be associated with activated innate immune system elements and impaired acquired immune system responses. The health relevance of these stress-related immune changes has been demonstrated in studies that have shown an association between chronic stress and increased susceptibility to the common cold, reduced antibody responses to vaccination, and delayed wound healing (Cohen et al. 1991 Glaser et al. 1992 Kiecolt-Glaser et al. 1995). In addition, stress, as well as depression, has been linked to increased morbidity and mortality in infectious diseases (e.g., HIV infection), neoplastic diseases (including breast cancer and malignant melanoma), diabetes, and cardiovascular disease (Evans et al. 2005 Fenton and Stover 2006 Leserman et al. 1999 Raison and...

Pglycoprotein Substrates

Resistance to chemotherapeutic drugs has been observed in orbital tumors. P-glycoprotein has been found in retinoblastoma, and when coexpressed with multi drug-resistance associated protein-1 (MRP1) there is poor prognosis with chemotherapy (41). P-glycoprotein has been identified in 12 of retinoblastomas following treatment by primary enucleation without any chemotherapy (42). P-gp has also been detected in ocular melanoma (42 ), and when present there is also a poor therapeutic outcome (43).

Pharmacology and pharmaceutics

Other applications Leukine has been effective in producing increases in normally functioning neutrophils, eosinophils, and monocytes in AIDS patients and patients with leukopenia. Leukine may prolong survival when used as adjuvant therapy in patients with stage III or IV malignant melanoma. Leukine has also been effective in abrogating chemotherapy-related neutropenia in cancer patients, with a reduction in the severity and duration of chemotherapy-induced myelosuppression.

Studies on optimization in vitro and in vivo characterization

Before the above study in the melanoma mice model, we have carried out detailed studies to characterize the in vitro and in vivo properties of PolyHb-tyrosinase (Yu and Chang, 2002, 2004a, 2004c, 2004e and 2006). This includes optimization of the method of preparation and in vitro and in vivo characterization of PolyHb-tyrosinase (Yu and Chang, 2004e). These studies showed that PolyHb-tyroinase can lower plasma tyrosinase in mice without causing vomiting and weight loss. Furthermore, polyHb-tyroinase retains its ability to inhibit the growth of melanoma cell culture and retains its ability to carry oxygen. This leads to the above study on the actual use of this preparation in a melanoma mice model. After optimization and in vitro and in vivo characterization of the preparation, we carried out the following studies. Next, we analyzed the effects of PolyHb-tyrosinase on the growth of melanoma cell culture. We cultured B16F10 melanoma cells in DMEM and added one of the following four...

Background and Historical Perspective

Inhaled therapies have existed for at least 5000 years (1). Modern drug therapy can be traced to the propellant-driven (also known as pressurized) metered-dose inhaler (pMDI) of the 1950s (2). The surge in interest that has arisen in the last decade relates to the chlorofluorocarbon (CFC) propellant ban and the development of biotechnology products. The observation that CFC propellants play a significant role in ozone depletion in the upper atmosphere (3), which in turn results in greater surface ultraviolet (UV) radiation and impact on public health, particularly the incidence of skin cancer, led to regulation in the late 1980s (4). In addition, the burgeoning biotechnology industry of the late 1980s and early 1990s actively sought alternative methods of delivering macro-molecular drugs, which were difficult to deliver in therapeutic doses by the oral or parenteral route (5). The urgent need for alternative methods explains the diversity of devices that have been described in the...

Effects of Longterm Oral Administration of Polymeric Microcapsules Containing Tyrosinase on Maintaining Decreased

Both groups of rats were maintained on a regular rat chow. In the test group, there was a slow decrease of plasma tyrosine level in the first 3 days, because of the time taken for the large intracellular pool of tyrosine to equilibrate with the extracellular pool. On day 4 there was a significant decrease in tyrosine level in the test group to 68.8 . By days 18 and 22, the systemic tyrosine levels decreased to 56.8 and 52.6 , respectively. Our result showed that three times daily oral administration can lower the tyrosine concentration in a rat's plasma, starting from day 4 to a level that, based on Meadow etal. 's (1982) tyrosine restricted diet study, would retard the growth of melanoma. However, unlike the group on the tyrosine restricted diet, the test group on oral treatment did not lose any weight. Instead, they gained weight with a weight gain curve identical to that of the control group (Fig. 7.11B). No abnormal effect or behavior was observed in both groups. In a separate set...

Therapeutic Applications of CpG Oligonucleotides

Since CpG ODNs have shown antitumor activity in many mouse models, they have been introduced into clinical trials to treat human cancer patients. After isolation of dendritic cells from patients treated with CpG ODNs, a Th1-like cytokine response could be detected, providing evidence for the immune stimulatory potency of the new drug candidates.52 B-class CpG ODNs have been studied in various cancer indications, including non-Hodgkin's lymphoma, cutaneous T cell lymphoma, basal cell carcinoma, breast cancer, renal cell cancer, melanoma and non-small-cell lung cancer (NSCLC).15,53 Furthermore, a B-class CpG ODN has shown promising results in a Phase II randomized controlled human clinical trial in patients with NSCLC. The response rate was improved from 19 in patients receiving standard chemotherapy to 37 in patients receiving a combination therapy of taxane-platinum plus CpG ODN.54 The one-year survival was improved from 33 to 50 when chemotherapy was combined with the CpG ODN....

Discussions on PolyHbTyrosinase and Tyrosinase Artificial Cells

Meadow's group show that tyrosine and phenylalanine restricted diets reduce the growth of melanoma and increase the survival of B16 melanoma-bearing mice (Meadow and Oeser, 1983 Fu et al., 1997). One of the main problems with these low amino acids diets is that they cause nausea, vomiting and malnutrition as well as weight loss in the severely ill patients. We showed that daily intravenous injection of PolyHb-tyrosinase can retard the growth of melanoma in mice without having the adverse effects of vomiting and weight loss of tyrosine restricted diet. Furthermore, the use of PolyHb-tyrosinase can reduce the plasma asparagines level to 15 as compared with 62 for tyrosine restricted diet. To avoid the need for daily intravenous injections, we have also studied the use of oral tyrosinase artificial cells. Oral administration does not have an adverse effect on the growth and body weight of the animal. It can effectively lower the systemic tyrosine in animals, but takes a longer time to...

Germanium modified organic compounds

Besides spirogermanium and germanium sesquioxanes, numerous other organo-germanium compounds have shown anti-tumour activity against experimental tumours. They include the octahedral complex (4)134 and some deca-phenylger-manocene (5) derivatives.135 The dimethyl derivative 4 (R1 Me) was cytotoxic in vitro towards HeLa cells, inhibited the solid form of B16 melanoma and IMC carcinoma (33 and 39 inhibition, respectively) and produced a complete remission of tumours in 50 of rats bearing a Walker 256 carcinosarcoma.134 The monomeric air-stable decaphenylgermanocene 5 has been synthesized. This compound produced 40 80 cure rates in mice bearing the fluid Ehrlich ascites tumour.135,136 Germanium and silicon derivatives of furfural semicarbazone and thiosemi-carbazone exhibited similar anti-tumour activities against the melanoma B16 in mice (40-48 inhibition of the growth).141 5-Trimethylgermyluracil, its silicon counterpart and their 1-(2-tetrahydro-furyl) derivatives display similar...

Drugs That Inhibit Microtubule Polymerization At High Concentrations

Several semisynthetic analogs of these alkaloids6 are also in clinical use, most notably vindesine, used mainly to treat melanoma and lung carcinomas and, associated with other drugs, to treat uterine cancers, and the nor-derivative vinorelbine, used for non-small cell lung cancer, metastatic breast cancer, and ovarian cancer. The fluorinated analog vinflunine is in clinical development.7

Free Radicals In Carcinogenesis And Apoptosis The Critical Balance

Melanoma cells, and H202 are reported to enhance tumor growth by inactivation of SH groups of caspases that regulate apoptosis.114 All these are involved in initiation, promotion, and progression of carcinogenesis (Figure 13.2).4 However, ROS can have a diametrically opposite effect and suppress or inhibit carcinogenesis (Figure 13.2). Generation of adequate amounts of ROS triggers tumor cell apoptosis by enhancing p53 expression and telomere shortening. Telomeres regulate cell division, and in human somatic cells, telomeres shorten with each cell division. However in tumors, telomeres are stabilized at constant length by the enzyme telomerase.115 H2O2 treatment of nonproliferating human MRC-5 fibroblasts was reported to accelerate the shortening of telomeres and reduce cell growth and differentiation.116

Genentechs UK patent 2119904 on tissue plasminogen activator tPA

The natural t-PA protein was a known substance having been previously isolated from the Bowes melanoma cell line. The amino-acid sequence of t-PA had not previously been determined, but one cannot patent a known substance just by being the first to determine its structure. In holding the patent invalid the court of first instance said that had Genentech been the first to discover t-PA, its decision would have been different. Since most of the initial applications of this technology have been aimed at producing naturally occurring proteins of known therapeutic value this observation was cold comfort for those using standard techniques in this field. The only consolation that this statement offers is that novel derivatives or analogues of t-PA or other proteins which show some advantage over the natural product cannot be so readily dismissed as unpatentable. In the Court of Appeal the recombinant product was held obvious first, because it was a known desirable objective on which a...

The European patent on tPA

The corresponding European patent 93619 issued in September 1989 (6), had a claim structure very different from that of the British patent. It relied mainly on process claims, such as A process which comprises preparing cDNA from mRNA extracted from the Bowes melanoma cell line and isolating from it a DNA sequence having the restriction pattern shown in Figure 4 hereof for the putative mature tissue plasminogen activator sequence and which encodes a 527 amino-acid polypeptide having human tissue plasminogen activator function.

Uses of the PCR in research and clinical diagnosis

Exfoliative cytology specimens can be collected by washing, scraping or aspiration techniques. These specimens could include cells found in urine, sputum, pleural effusions or from uterine cervix. The analysis of such specimens by the PCR is being used clinically to obtain a rapid indication of the presence of neoplastic disease, e.g. following cervical smear testing (McPherson et al., 1991). In other instances, the PCR has been used in the identification of presurgical lymph node metastases in melanoma patients (Schwurzer-Voit et al., 1996) and to confirm diagnosis of acute promyelocytic leukaemia and chronic myelogenous leukaemia by detecting specific chromosomal translocations (Drexler et al., 1995 Wujcik, 1996). The technique has also been used to monitor response of these diseases to chemotherapeutic agents and to predict disease progression. Recently, researchers at the Columbia Presbyterian Medical Center in New York City have patented a new test for thyroid cancer (Lewis,...

MAb and MAbbased Constructs

Successful results have been observed using anti-IL-2 receptor MAb in T-cell acute lymphoblastic leukaemia (ALL) 115,116 .An early trial using a MAb against CD10 showed dramatic reductions in peripheral blood leukaemia cells in three patients 115 . A MAb against the Lewis Y antigen which is abundantly expressed on the surface of cells from several human carcinomas, induced four minor responses in 12 patients with advanced breast cancer 58 . Finally, MAbs against the asialoganglioside antigens, GD2 and GD3, which are present on tumours of neuroectodermal origin including melanoma and neuroblastoma, were successfully applied in a number of studies 117-121 . Humanized and chimerized MAbs have been developed for the treatment of non-Hodgkin lymphoma, renal cell carcinoma, ovarian carcinoma, breast cancer, melanoma, and neuroblastoma 117,119,120,123,124 . Patients with relapsed or refractory myeloid leukaemias that have been treated with HuM95, did not develop significant HAMA responses 59...

SNP and Gene Expression Profiling

With advances in microarray technology, an abundance of new and challenging applications has arisen on several other biomedical fronts. For example, in cancer biology, cancer classification has been based historically on morphological appearance. But tumors that are similar in appearance histopathologically can follow significantly different clinical courses and show different responses to therapy. In 1996, Trent's laboratory drew attention to the use of DNA micro-arrays as a tool to pinpoint gene variants in melanoma cancer cell lines by monitoring gene expression patterns.23 The potential importance of this technique was brought into sharper focus by Golub and colleagues who used microarrays to As a general approach to a better understanding of the pathogenesis of cancer based on genetically defined molecular markers, gene expression profiling with microarrays has been fruitful for the identification of new classes of cancer (class discovery) and for assigning tumors to known...

Biological Background

Inherited defects in the NER process cause serious repair disorders xeroderma pigmentosum (XP), with extreme risk of ultraviolet-induced skin cancer, and Cockayne syndrome. NER functions by a cut-and-paste mechanism in which cisplatin damage recognition, local opening of the DNA helix around the lesion, damage excision, and gap-filling occur in successive steps (12) (Fig. 1). NER is composed of two sub-pathways global genome NER (GG-NER) and transcription-coupled NER (TC-NER) share the same core mechanism but differ in the way lesions are recognized (13).

Antiproliferative and Apoptotic Effects

A prerequisite for unregulated growth in cancer cells is an acquired defect in one or more proteins that serve as check points for normal cell cycle progression. IFN-a and IFN-b can affect all phases of the cell cycle M, G1, and G2 112 . The cumulative prolongation of the cell cycle can result in cytostasis, an increase in cell size, and apop-tosis 113 . IFN-a treatment results in down-regulation of cyclin D3 and cyclin D-cdk4 and cyclin D-cdk6 kinase complexes, and inhibition of hyperphosphorylation of retinoblastoma (Rb) protein, thus suppressing cell cycle progression 114-116 . IFN-a has been shown to induce apoptosis by up-regulating Fas Fas ligand expression in multiple myeloma cells, chronic myel-ogenous leukemia, and gliomas 117-119 . IFN-b, although not capable of inducing Fas expression, can induce apoptosis in multiple myeloma and melanoma by in

Activation of the RacGTPase Rac1 Inhibits Apoptosis in Human Tumor Cells

Racl, one of the main subunits of the NADPH oxidase in nonphagocytic cells, is also one of the downstream targets of the oncogene ras, overexpression and mutations of which have been described in about 30 of all human tumors 65,66 . Interestingly, mitogenic signal triggered by Ras in a fibroblast cell line was shown to be mediated by Rac-dependent intracellular production of O2 , thereby lending support to the hypothesis that O2 acts as an important proliferative signal in tumor cells 11,12 . However, our data demonstrating the apoptosis inhibitory activity of O2 led us to hypothesize that in addition to triggering proliferation, activation of the Ras protein may also result in inhibition of apoptosis through Rac-mediated O2 production in tumor cells. Indeed, expression of a constitutively active form of Racl in the human melanoma cells M14 significantly inhibited tumor cell response to apoptotic triggers such as staurosporine and etoposide. Moreover, results of experiments performed...

The Development of Photodynamic Therapy

Photodynamic therapy was first investigated at the start of the twentieth century and the story of its discovery is an interesting example of scientific enquiry 5 . Oscar Raab, a student of Professor Hermann von Tappeiner at the Ludwig-Maximilian's University in Munich, had been conducting experiments on the toxic effects of acridine on paramecia (single cell organisms). He was surprised to find that in one experiment paramecia survived for 1.5 hours while in another experiment under identical conditions the paramecia survived for 15 hours. Raab, intrigued by his results, went back to his lab books and noted that there had been a heavy thunderstorm on the day of the second experiment, making the laboratory darker than normal. This led him to consider whether light had had an effect on the toxicity of the dye. His research group subsequently went on to discover that both light and oxygen were necessary components of this effect and coined the term photodynamic. Raab and his colleagues...

HSP90 Inhibition as an Anticancer Strategy Novel Approaches and Future Directions

Abstract Heat shock protein 90 is an ATP-dependent molecular chaperone involved in the maturation and stabilisation of a wide-range of proteins in both the presence and absence of cellular stress. Within the ever expanding list of HSP90 client proteins is a broad range of bona fide oncoproteins. This has thrust HSP90 into the spotlight as an exciting anticancer drug target. Several natural product and semi-synthetic derivatives have been described which inhibit the activity of HSP90 by preventing the association of the N-terminal domain with ATP. This approach is exemplified by 17-AAG which is the first-in-class HSP90 inhibitor to complete phase I clinical trial and provide proof-of-concept for this approach with the observation of responses in patients with malignant melanoma, multiple myeloma, prostate and breast carcinoma. Research is now focused on the design of more potent and drug-like synthetic small-molecule inhibitors. This article provides a personal

Maria Scatolini Maurizia Mello Grand Francesco Acquadro Francesca Guana and Giovanna Chiorino Fondo Edo Tempia Biella

In our study we analyzed 55 biopsies from common nevi (n 22), primary radial growth phase malignant melanoma (n 15), primary vertical growth phase malignant melanoma (n 13) and melanoma metastasis (n 5). Global gene expression profiling of the tissues was performed using whole genome oligo-swap microarrays with a dye-swap duplication scheme. All the samples were also sequenced to look for BRAF mutations. The first goal of our study was to identify candidate genes of melanoma progression and candidate markers of melanoma metastasis. The second goal was to look for any correlation between BRAF mutation and patient phototype or sun exposure in nevi and melanomas. The third one was to compare the gene expression profiling of nevi and melanomas with or without V599E mutation on BRAF exon 15 to find any alternative way of melanoma development not involving the MAPK cascade signaling. Results will be presented and discussed.

Uvinduced Photodamage And Photoprotection

UVR is the main etiological agent for most of the skin cancer incidence and a key factor responsible for photoaging and photodamage (Gonzalez et al., 2008). UV spectrum reaching earth's surface has been classified as UVB (290-320 nm) and UVA (320-400 nm). UVB causes acute sunburn, DNA mutation, or even cancer by its absorbance in the epidermis, whereas the longer wavelengths of UVA region can penetrate much deeper into the skin. Continuous exposure to UV irradiation (both UVA and UVB) leads to skin cancer and other photoaging complications, which are typically mediated by the reactive oxygen species (ROS), generated in the oxidative pathways (Dummermuth et al., 2003 Pallela et al., 2010). Normal skin cells

Gene therapy the real diseases

Recovered from excised tumours in adoptive transfer protocols (Rosenberg, 1991). Hence, immune cells infiltrating certain human tumours, principally melanoma, renal cell cancers and colorectal cancers, have been grown ex vivo to high numbers and reinfused into patients. The rationale is that the immune cells presumably have natural tumour recognition capabilities as they were originally isolated from growing tumours when reinfused they should circulate through the body and concentrate in metastatic deposits expressing whatever antigens they are primed to recognise. Initial patient trials using non-T non-B-cell tumour-infiltrating lymphokine-activated killer (LAK) cells in adoptive immunotherapy (Rosenberg, 1984) were superseded by the use of a more specific T-cell population of IL-2 expanded tumour-infiltrating lymphocytes (TILs) (Rosenberg et al., 1988a Ioannides and Whiteside, 1993). Although these trials have reported only limited clinical success, TIL populations are now being...

Antitumour Prescreening

Table 22.1 ID50 values (ng ml) of oncology drugs doxorubicin (DOX), cisplatin (CPT), 5-fluorouracil (5-FU), methotrexate (MTX) and etoposide (ETO) against seven cancer cell lines of human origin, MCF-7, EVSA-T (mammary cancers), WIDR (colon cancer), IGROV (ovarian cancer), M19 MEL (melanoma), A498 (renal cancer) and H226 (non-small-cell lung cancer) Table 22.1 ID50 values (ng ml) of oncology drugs doxorubicin (DOX), cisplatin (CPT), 5-fluorouracil (5-FU), methotrexate (MTX) and etoposide (ETO) against seven cancer cell lines of human origin, MCF-7, EVSA-T (mammary cancers), WIDR (colon cancer), IGROV (ovarian cancer), M19 MEL (melanoma), A498 (renal cancer) and H226 (non-small-cell lung cancer) a panel of human tumour cell lines.15 27 This was also the procedure used when organotin compounds were tested by the Rotterdam Cancer Institute. The seven human tumour cell lines comprising the panel were MCF-7 and EVSA-T (two mammary cancers), WIDR (a colon cancer), IGROV (an ovarian cancer),...

Chemotherapy And Immunotherapy Of Renal Carcinomas

In melanoma, another promising target for immunotherapy, immune responses are directed against proteins particular to melanocytes and to cancer-testis antigens ectopically expressed in the cancer ( -12.5). In renal carcinoma, oncofetal antigens, i.e. proteins normally expressed only during fetal development and down-regulated in adult kidney, may represent one type of target. More broadly, antigens recognized by immune cells in RCC are derived from proteins as part of the constitutive hypoxia response (Table 15.5), particularly in the conventional type. For instance, a promising cell membrane antigen recognized by the monoclonal antibody G250 is expressed on the surface of essentially every renal carcinoma (of various subtypes), but is not at all detectable in normal kidney. This antigen has turned out to be part of the CA9 carbonic anhydrase, which is induced several-hundred fold in clear cell RCC as a consequence of constitutive HIF1 activation.

Clinical pharmacology The interferons

Therapeutic response The percentage of patients with hairy-cell leukemia who required red blood cell or platelet transfusions decreased significantly during treatment with Intron A, and the percentage of patients with confirmed and serious infections declined as granulocyte counts improved. Intron A therapy produced a significant increase in relapse-free and overall survival in patients with malignant melanoma. Patients receiving the combination of Intron A therapy plus che F. Role in therapy According to Micromedex, Intron A is the agent of choice for the treatment of malignant melanoma (surgical adjuvant) and chronic hepatitis B. It is also the drug of choice for chronic hepatitis C in combination with ribavirin. The combination is available under the name Rebetron. Intron A is an alternative (unresponsive intolerant patients) to pentostatin in hairy-cell leukemia, topical podophyllin regimens in condyloma acuminata, and standard regimens in multiple myeloma.

Modulating the Association ofHSP90 CoChaperones

The potential to simultaneously deplete malignant cells of multiple client proteins and to modulate all six hallmark traits of cancer by inhibiting a single protein target has propelled HSP90 into the spotlight as an exciting anticancer drug target. Natural product HSP90 ATPase-inhibitors have been fundamental in elucidating the mechanism of action of the molecular chaperone. The geldanamycin analogue 17-AAG has completed phase I trials and provided proof-of-concept for HSP90 inhibition in the clinical setting. 17-AAG has shown early promise as the first-in-class HSP90 inhibitor with responses being observed in melanoma, breast and prostate carcinoma and phase II trials have now been initiated. A phase III study of 17-AAG plus trastuzumab in trastuzumab-refractory, ERBB2-positive tumours has been initiated. Phase III trials have also been instigated for the combination of 17-AAG and borte-zomib for patients with multiple myeloma, where promising clinical activity has been seen in...

Potential of antisense oligonucleotides as drugs

In animal studies, targeting with DNA modified with methylphos-phonate groups to a specific gene - c-myc - has been found to reduce lymphoma growth (Wickstrom, 1997). In this case, the antisense was injected through the tail vein. Continuous application to mice with a micro-osmotic pump also reduced the likelihood of developing tumours. Restenosis in pigs has also been inhibited with anti c-myc phosphoro-thioated antisense (Shi et al., 1994). Wound healing and, in particular, the effects of scarring are influenced by the application to mice of antisense molecules against the growth factor TGF- 1. Similarly, c-H-ras-transformed cells, when treated with antisense and injected into mice, led to a great reduction in tumorigenesis (Gray et al., 1993). In vivo tumour growth in mice has also been suppressed using antisense against the R1a gene, which encodes one of the regulatory units of protein kinase type A (Yoon et al., 1997). Targeting the basic fibroblast growth factor and its receptor...

Antitumor agents targeted at lysosomes

Kahalalide F is a depsipeptide derived from the sea slug Elysia rufescens. This compound alters the function of the lysosomal membranes, a mechanism that distinguishes it from all other known antitumor agents. Other mechanisms of action are inhibition of the TGF-a expression, blockade of intracellular signaling pathways downstream of EGF and ErbB2 receptor family, and induction of non-p53-mediated apoptosis. Kahalalide F is currently in Phase II clinical trials in hepatocellular carcinoma, non-small cell lung cancer (NSCLC), and melanoma, and is also being evaluated for the treatment of severe psoriasis. In these studies, kahalalide F has shown limited activity but an excellent tolerability profile that merits further clinical evaluation in combination with other anticancer compounds.

Carcinogenesis a multistage process

While the genetic and morphologic analysis of human neoplasia has impressively demonstrated the gradual development of cancer 3 , our knowledge of the underlying mechanisms is mainly based on animal experiments which allow a dissection of tumo-rigenesis into distinct stages. A classical model of multistage carcinogenesis is provided by skin cancer in mice 1,2,5 , where each of the stages of carcinogenesis can be induced separately under strictly controlled conditions, e.g. initiation and malignant progression by genotoxic carcinogens and promotion by so-called tumor promoters, which are a subclass of non-genotoxic carcinogens. However, the conditions of tumor promotion may be created by any situation which leads to repeated release of both mitogenic and anti-mitogenic signals in the tissue. In fact, the effects of many non-genotoxic carcinogens belong to this category. In particular, in the mouse skin model, the most active tumor promoters are also at the same time potent irritants

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.

Molecular characterization

The first galanin receptor (GalRl) was cloned by Habert-Ortoli et al. from Bowes human melanoma cell line (Habert-Ortoli et al. 1994), a little more than a decade after the discovery of the endogenous ligand galanin This discovery was followed by the cloning of the rat GalRl homologue in 1995, and two more subtypes (GalR2 and GalR3) have since then also been cloned from several species (Ahmad etal. 1998 Bloomquist etal. 1998 Borowsky etal. 1998 Burgevin et al. 1995 Fathi et al. 1997, 1998a Howard et al. 1997 Iismaa et al. 1998 Jacoby etal. 1997 Kolakowski etal. 1998 Lorimer andBenya 1996 Lorimer etal. 1997 Pang etal. 1998 Parker etal. 1995 Smith etal. 1997 Sullivan etal. 1997 Wang etal. 1997a-c).

Possible Regulatory Mechanism of Gene Expression in TAMs or Cancer Cells After the TAMCancer Cell Interaction

Paracrine regulation between cancer cells and TAMs has been observed and may play an important role in the tumor angiogenesis 82, 83 . Furthermore, using macrophage-cocultured cancer cells to sensitize naive cancer cells, it was demonstrated that not only paracrine, but also autocrine regulation was seen in the lung cancer cells TAMs cocultures 85 . This autocrine effect is also seen with different lung cancer cell lines 82 , suggesting that autocrine regulation of IL-8 expression is a rather general phenomenon in the lung cancer cells. This suggests that autocrine regulation might play a crucial role in the tumor progression, particularly in cancer cells that have not interacted directly with TAMs but have been stimulated by TAM-activated cancer cells. It is well known that TNF-a activates angiogenic factors in several human tumor cell types and in vascular endothelial cells 84, 86 , and a previous report hinted that TNF-a and IL1-a, produced by activated macrophages, are involved in...

Effects of eicosanoids on tumor cell metastasis

Pharmacologic evidence points to the activation of PKCs as mediators of 12(S)-HETE-induced integrin expression 161,162 , In addition, PKC-mediated phosphorylation of cytoskeletal proteins may lead to the cytoskeletal rearrangements induced by 12(S)-HETE 163 , Using murine B16 amelanotic melanoma cells as a model system, cell spreading on the extracellular matrix protein fibronectin was shown to be due to high-affinity binding of 12(S)-HETE to the cell surface, accompanied by hydrolysis of inositol phospholipids and translocation of PKC from the cytoplasm to the plasma membrane and to focal adhesion plaques. These responses were antagonized by the linoleic acid metabolite 13(S)-HODE 164 , Among the different HETEs the pro-metastatic effects seem to be restricted to 12(S)-HETE which is the product of at least three 12-lipoxygenase isozymes, i.e. the platelet-, the leukocyte- and the epidermis-type 12-lipoxygenases 157,165 . Several tumor cell lines and solid tumors of animals and men...

Integrin Ligands As Modulators Of Cell Adhesion

Are expressed only on leukocytes whereas the integrins a2 31 a3 3i, a5 31, a6 3 , and av 33 are expressed on endothelial cells. In platelets, aIIb 33 (known also as GPIIb IIIa) is the major integrin. Furthermore tumour cells, for example human melanoma cells, express avb3 (vitronectin receptor) which promotes a survival signal protecting these cells from apoptosis (programmed cell death) in the three-dimensional collagen matrix (Montgomery et al., 1994).

Why Integrin av fi3 Targeted Radiopharmaceuticals

Integrins are a family of proteins that facilitate cellular adhesion to and migration on the extracellular matrix proteins found in intercellular spaces and basement membranes. They also regulate cellular entry and withdraw from the cell cycle. Integrin avfi3 is a receptor for a variety of extracellular matrix proteins with the exposed RGD tripeptide sequence 48-51 . These include vitronectin, fibronectin, fibrinogen, lamin, collagen,Von Willibrand's factor, osteoponin, and adenovirus particles. The expression of integrin avfi3 enables a given cell to adhere to, migrate on or respond to almost any matrix protein it may encounter. Despite its promiscuous behavior, integrin avfi3 is generally expressed at low levels on epithelial cells and mature endothelial cells. It has been reported that in-tegrin avb3 is highly expressed on the neovasculature of tumors, including os-teosarcomas, neuroblastomas, glioblastomas, melanomas, lung carcinomas, and breast, prostate, and bladder cancers...

Polynuclear Platinum Compounds

Bifunctional DNA-binding agent with an overall 4+ charge. Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including responses in melanoma, pancreatic cancer and lung cancer. Objective responses in Phase II were verified in relapsed ovarian cancer and non-small-cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. The interactions of anti-tumor polynuclear platinum compounds with target DNA (for reviews, see for instance Refs 11, 44) are distinct from the mono-nuclear-based cisplatin family and, indeed, unlike those of any DNA-damaging agent in clinical use. The ability of BBR3464 to induce DNA adducts such as long-range delocalized intra- and inter-strand cross-links45 which are not produced by conventional mononuclear platinum compounds suggests that BBR3464 may avoid, at least in part, the classical mechanism of cisplatin resistance related...

Global Views of Cancer Genetics

The molecular classification of tumors is central to advances in the treatment of these cancers as a means of maximizing the efficacy and minimizing the toxicity of specific therapies targeted to distinct tumor types. Attempts to identify distinct tumor types by gene expression monitoring using DNA microarrays began in the 1990s. Joseph DeRisi and colleagues were among the first to demonstrate that such microarrays could provide a tool for cancer identification.110 They used a high-density microarray composed of 1161 DNA elements to search for differences in gene expression associated with tumor suppression of a melanoma cell line and they identified a number of alterations in the expression of genes specific to the tumorigenic phenotype of those cells. Their results suggested that DNA microarrays could be used as a tool to define alterations in gene expression associated with a specific cancer, and that they might provide a deeper understanding of pathognomonic molecular derangements...

Microarrays a Tool for Gaining Insight into Cancer Genomics

Nology to classify and subclassify leukemia, lymphoma, melanoma, and breast cancer.111-118 Todd Golub and co-workers set out to develop a systematic analytical approach to class prediction using gene expression profiles to distinguish acute leukemia types whose histological appearance was highly similar.111 Golub et al. prepared RNA from mononuclear cells isolated from bone marrow samples obtained from 27 acute lymphoblastic leukemia (ALL) and 11 acute myelogenous leukemia (AML) patients and produced microarrays containing probes for 6817 human genes. In this case, a microarray was designed to distinguish these two forms of leukemia. This distinction is critical to successful therapy because chemotherapy regimens for ALL generally contain corticoste-roids, vincristine, methotrexate, and L-asparaginase, whereas most AML therapies rely on regimens that contain daunorubicin and cytarabine. The goal was to create an array consisting of 50 predictor genes based on all 38 samples. The 50...

Antitumour properties of gold drugs

The potential anti-tumour activity of gold complexes has been demonstrated in a number of experimental models but, to date, no gold complexes have entered clinical trials.56 Auranofin (6) was shown to be cytotoxic towards Hela cells.57 It was also active against P388 leukaemia in vivo, a well-documented primary screen for anti-tumour activity,58 whereas the oligomeric Au(I) thiolates were inactive.59,60 However, 6 was inactive in subsequent tests using solid tumour models.61 A series of tertiary phosphinegold(I) complexes with thiosugar ligands was found to be active against both the P388 leukaemia and B16 melanoma, in vitro, and P388, in vivo.55 In general, phosphinegold(I) thiolates were more cytotoxic than gold thiolates as well as their phosphinegold(I) chloride analogues, indicating the importance of the phosphine ligand and the thiolate for activity, and the investigation of Auranofin analogues continues today (see later). Besides demonstrating the potential of Au(I) complexes...

Ernesta Fagiani Giuseppina Giardina Giovanni Germano Micaela Quarto Maria Capra Lucilla Luzi and Luisa Lanfrancone

RaLP is a recently isolated member of the Shc family of adaptor proteins, that shares the same modular organization (CH2, PTB, CH1, and SH2 domains). We have demonstrated that it is a physiological substrate of various receptor tyrosine kinases. Analysis of RaLP expression in normal adult tissues and in a panel of 350 primary tumors of different histological origin showed selected expression in melanomas. Moreover, during melanoma progression RaLP is expressed in vertically growing and metastatic melanomas, but not in nevi and radially growing melanomas, thus suggesting a role of RaLP in the invasive and migratory phenotype of this tumor. Down-regulation of RaLP expression in melanoma inhibits cell migration and induces apoptosis. Primary cultures of normal melanocytes are not transformed by RaLP overexpression. Together, these data suggest that increased expression of RaLP protein in metastatic melanomas is essential, but not sufficient, to maintain a transformed phenotype. Analysis...

Tetrahedral goldI complexes

From the data obtained in this study it was apparent that the nature of the X counter ion in Au(R2PYPR2) X had little influence upon their potency against B16 melanoma.64 The most active complexes had phosphorus-bound phenyl groups, i.e. Au(dppe)2 + (10). It was suggested that the reduced potency of complexes with phosphorus-bound ethyl substituents could be correlated to their enhanced reducing ability,64 i.e. ability to be oxidized to phosphineoxides.

Ketoconazole Safety and side reactions

Gynecomastia detected as a side effect of ketoconazole treatment led to a thorough investigation of its interference with sterol metabolism as a consequence, treatment of human breast cancer, 6.383, 6.384 human pancreatic carci-noma, 6.384 human colonic adenocarcinoma, 6.384, 6.385 and leukemia has been attempted. 6.384, 6.386 Beneficial effects of ketoconazole on melanoma tumor, 6.387 rat pituitary cells, 6.388 and on the metastasis of pancreatic adenocarcinoma have been seen. 6.389 In particular, treatment of human prostate can-cer, 6.320, 6.383, 6.384, 6.390, 6.391, 6.392 seems hopeful, though the drug has not been generally accepted as a remedy for hormone-related cancers. 6.392 The potential activity against the latter is connected with a transient decrease of plasma testosterone and 4-androstenedione levels during treatment, and an increase in plasma 17-hydroxyprogesterone after a high-doses regime of ketoco-nazole.

Gene Therapy and Cancer

Modified tumour cells transduced with IL-2, TNFC and GM-CSF into melanoma, colorectal, renal cell carcinoma, neuroblastoma and breast cancer cells are underway (39). Another approach involves rendering tumour cells more immunogenic through the transduction of co-stimulatory molecules such as B7 which enhances T cell activation. While transfection with B7 inhibits tumour growth, covaccination with the cytokine IL-2 has been found to significantly enhance antitumour activity (46, 47). In attempts to circumvent the high cost and times required for ex vivo production of vaccines a number of in vivo strategies have also been designed. Direct injection of adenovirus vectors encoding IL-2 and IL-12 into established murine breast cancer tumours (48) and metastic colon cancers (49) caused significant suppression of tumour growth.

HSV1 Based Vectors for Gene Therapy of Nervous System

Multiple immediate early gene-deleted nonreplicadve HSV-1 vectors are characterized by high efficiency of transduction of several different host species and cell types, both dividing and non dividing, including various tumor as well as endothelial cells.23,204207 Different replication-defective HSV vectors have been produced that deliver anti-cancer transgenes to tumor cells such as melanoma,43 gliosarcoma,205,21)8,209 or glioblastoma.210 Two or more therapeutic molecules, acting additively or synergistically, can thus be expressed at comparable levels by cells transduced with a combination vector, which is clearly an advantage in comparison with co-administration of two or more vectors encoding a single transgene and also in comparison with co-expression of two molecules, separated by IRES sequences, by a unique vector.

CXC Chemokine Receptors 1621 CXCR4

Muller et al. performed a comprehensive examination of chemokine receptor expression on a series of breast cancer and melanoma cell lines (2). Using quantitative RT-PCR and specific probes for CXCR1-5, CCR1-10, CX3CR1, and XCR1, seven breast cancer cell lines expressed mRNA primarily for CXCR4, CXCR2, and CCR7. In comparison with normal mammary epithelial cultures, CXCR4 and CCR7 were consistently elevated in malignant cell lines. Like breast cancer cell lines, melanoma cell lines also expressed high levels of CXCR4 and CCR7, but in addition, these cells expressed high levels of CCR10 compared with normal primary melanocytes. Examination of pleural effusions from breast cancer patients, primary invasive lobular carcinomas, or ductal carcinomas also revealed heightened expression of both CXCR4 and CCR7 mRNA in malignant tissues compared with normal mammary gland. CXCR4 expression in primary tumors, axillary lymph nodes, and pulmonary and hepatic metastases was confirmed by...

Expression of reteplase in E coli

A complementary DNA library from a Bowes melanoma cell line was screened with a mixture of three oligodeoxynucleotides which were designed on the basis of the published t-PA sequence (26). A full-length t-PA complementary DNA clone was reconstituted from several overlapping clones. The coding sequence for the finger, EGF and kringle domains of the t-PA (nucleotides 199-714) was removed according to the intron-exon organization of the t-PA gene (31). The coding sequence of reteplase was introduced into the vector plasmid pKK223-3 as previously described (32). The resulting plasmid pA27 fd was introduced into E. coli K12 C600+ by transformation (33). The production level was improved by cotransformation with the pUBS520 plasmid containing the DNA Y gene (34).

Relevance of an Allosteric Pakl Inhibitor

Elevated Pak activity has been observed in a number of highly invasive cancer cells, suggesting that Pakl may also play a role in the cell motility underlying metastasis. Expression of constitutively active Pakl increases the motility of breast cancer-derived MCF7 cells (Vadlamudi et al. 2000). Conversely, expression of a kinase-dead Pakl mutant resulted in a three-fold decrease in migration of MDA-MB-435 melanoma cells (Adam et al. 2000). The role of Pakl in mediating cell migration may involve Pakl phosphorylation of the cytoskeletal signaling protein LIM kinase (LIMK), which increases LIMK activity ten-fold (Edwards et al. l999). Activated LIMK phosphorylates and deactivates the F-actin severing protein cofilin, leading to changes in actin cytoskeletal dynamics (Arber et al. l998 Yang et al. l998). Indeed, LIMK activity has been shown to be required for migration in breast cancer-derived cells (Yoshioka et al. 2003), highlighting the role of this Pakl substrate in tumor cell...

The Interleukins Aldesleukin129

Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma in adults. It is also indicated for the treatment of metastatic melanoma in adults. Research is under way on the use of aldesleukin for the treatment of various cancers (including head and neck cancers), treatment of acute myelogenous leukemia, and adjunct therapy in the treatment of Kaposi sarcoma. Renal and hepatic function is typically impaired during therapy with aldesleukin, so interaction with other drugs that undergo elimination by these organs is possible.

Miscellaneous Agents Hydroxyurea

In CML, HU largely has been replaced by imatinib. HU has produced anecdotal, temporary remissions in patients with advanced cancers (e.g., head and neck or genitourinary carcinomas, melanoma). HU has been incorporated into several schedules with concurrent irradiation, as it can synchronize cells into a radiation-sensitive phase of the cell cycle.

Macrophage Recruitment at the Tumor Site

Macrophage Pharmacological

Along with the supposed protumoral role of TAM, the local production of chemokines and the extent of TAM infiltration have been studied as prognostic factors. For example, in human breast and oesophagus cancers, CCL2 levels correlated with the extent of macrophage infiltration, lymph-node metastasis and clinical aggressiveness (Azenshtein et al. 2002 Saji et al. 2001). In an experimental model of nontumorigenic melanoma, low-level of CCL2 secretion, with physiological accumulation of TAM, promoted tumor formation, while high CCL2 secretion resulted in massive macrophage infiltration into the tumor mass and in its destruction (Nesbit et al. 2001). In pancreatic cancer patients, high serum levels of CCL2 were associated with more favourable prognosis and with a lower proliferative index of tumor cells (Monti et al. 2003). These biphasic effects of CCL2 are consistent with the macrophage balance hypothesis (Mantovani et al. 1992) and emphasise the concept that levels of macrophage...

MTcLabeled Integrin avb3 Receptor Antagonists for Tumor Imaging

It has been reported that integrin avb3 is highly expressed on the neovascula-ture of tumors, including osteosarcomas, neuroblastomas, glioblastomas, melanomas, lung carcinomas, breast, prostate, and bladder cancers 107-112 . A recent study showed that integrin avb3 is overexpressed not only on endothelial cells but also on tumor cells in human breast cancer xenografts 113 . The expression of integrin avb3 correlates with tumor progression in melanoma, glioma, and ovarian and breast cancers 107-113 . The highly restricted expression of integrin avb3 during tumor invasion and metastasis presents an interesting molecular target for diagnosis of rapidly growing solid tumors 104,114,115 .

Cyclopropylindole Alkylating Agents

Wzory Haftow

Sin,80 U-80224, and KW-218982 may be mentioned. Among these compounds, the water-soluble prodrug KW-2189, which is activated by carboxyl esterases, is the most advanced one, having undergone Phase II clinical trials in patients with advanced malignant melanoma.83 Hybrid compounds containing the cyclopropy-lindole fragment or its precursors and minor groove binding distamycin portions have also been prepared.84

Implication of TAMs in Immunotherapy of Human Cancers

The second approach is to use gene transfer to induce and enhance the antitumor effect of TAMs. Recently, genetic modification of tumor cells with cytokines, adhesion molecules, or MHC molecules has resulted in activation of immune cells, induction of immune responses, and facilitation of cancer cell recognition and killing. Dranoff et al. 115 showed that transfection of the GM-CSF gene into murine melanoma cells initiated an eVective and long-lasting anti-tumor response. Sanda et al. 116 also showed that vaccination with prostate cancer cells transfected with GM-CSF resulted in a significant increase in tumor-free survival of mice inoculated with the tumor. Morita et al. 117 showed that transfection of M-CSF into Lewis lung carcinoma cells prolonged the survival of mice injected with the transfected carcinoma cells compared to those injected with nontransfected cells and prevented lung metastasis. Dong et al. 118 showed that inoculation of mice with human prostate cancer cells...

Anti Cancer Effect Of Tulasi Leaves In Lung Cancer

Ursolic acid, a triterpene constituent of Ocimum sanctum, protected the rat liver microsomes in vitro against free-radical-induced lipid peroxidation.177 In animal studies, ursolic acid exhibited remarkable inhibitory activity against tumor promotion.178 Topical cosmetic preparations containing ursolic acid and its isomer oleanolic acid are proprietary products in Japan, and both products are reported to be useful in skin cancer therapy.179 The foregoing data open a tremendous possibility that Ocimum sanctum or its constituents may hold promise as adjuncts to human radiation therapy.

Antitumour Effects of Botanical Polysaccharides

Acemannan Macrophage Activation Pictures

Oral administration of exopolysaccharides from rice bran fermented with L. edodes induced the activation of NK cells in a dose-dependent manner and prolonged the life span of mice transplanted with Sarcoma-180 cells or B16 Bl6 melanoma cells 304 . Lentinan increased the cytotoxic activity of macrophages for metastatic lesions 31 , and this activity was suppressed by pretreatment of experimental animals with carrageenan, an anti-macrophage agent 305 (Figure 6.5). Similarly, schizophyllan and its soluble P-(1,6)-branched derivatives also activated the antitumour activity of macrophages 306 . Polysaccharides isolated from the mushroom G. frondosa increased IL-2 production in patients with lung and liver cancer, presumably as a result of macrophage activation 22 . These polysaccharides have been reported to activate macrophages, dendritic cells and T cells and to activate the cytotoxic activity of NK cells against YAC-1 cells through the production of IL-12 by macrophages 307 ....

Chemokines and Cancer

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

National Cancer Institute Ncis 60cell Screening And Gene Expression Data

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

Targeting Bcell Lymphoma

B-cell lymphoma 2 (Bcl-2) is a key inhibitor of apoptosis. Over-expression of Bcl-2 is a key event in the pro-survival of a number of cancers, ranging from solid tumours to leukaemias,76 and several studies have described that overexpression of Bcl-2 is linked with chemoresistance.77 This coupling has been found for, e.g., prostate cancer78 and malignant melanoma.79 High levels of Bcl-2 expression are collectively found to be associated with malignant phenotypes, bad prognosis and resistance to therapy, and Bcl-2 is therefore an interesting target for therapeutic intervention. For a detailed discussion of the function of Bcl-2 as well as of the development of a PS ON targeting Bcl-2 (Genasense) see Chapter 2 . Here, we present the main findings of our pre-clinical pharmacology studies that formed the basis for the clinical trial with SPC2996 (vide infra). SPC2996 is a 16-mer gapmer directed against the first six codons of the Bcl-2 transcript. SPC2996 downregulated the Bcl-2 mRNA in...

Association Between TAM Density and Patient Prognosis

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 with MVD and vascular endothelial cell growth factor (VEGF) protein expression in 249 patients with invasive ductal carcinoma. Takanami et al. 22 demonstrated that TAM infiltration was associated with MVD angiogenesis in pulmonary adenocarcinoma. Other studies showed that TAM density was associated with expression of angiogenesis factors, including...

Gene therapy in the clinic

GM-CSF has poor tumour growth-inhibiting effects, but vaccination with irradiated GM-CSF-transduced cells can induce long-lived systemic (T cell-mediated) anti-tumour immunity in a number of murine model systems. Based on these findings, Dranoff et al. (1993) have initiated a trial for the vaccination of patients with advanced melanoma using autologous (irradiated) melanoma cells transduced with the GM-CSF gene. In addition, Simons's group has started two clinical trials using irradiated autologous tumour cells transduced with the GM-CSF Successful and reproducible ex vivo gene transfer into explanted tumour cells has often proved to be difficult because of variability between tumour biopsy samples from different patients and their resistance to ex vivo culture. An alternative strategy has been to introduce the cytokine genes into a different cell type (cultured fibroblasts, for example), which can then be inoculated into the tumour mass or mixed with autologous tumour cells and...

Marine Spindle Toxins As Potential Anticancer Drugs

Based on the successes and limitations of taxol as an anticancer drug, a number of tubulin-targeted marine toxins have been considered as a source of new anticancer drugs, some of which have entered clinical trials. The synthetic analogue of crypto-phycin 1, LY355703 ( cryptophycin 52), has entered phase II clinical trials (Sessa et al. 2002 Stevenson et al. 2002). Tasidotin, a dolastatin 15 derivative, entered phase I as a treatment for solid tumors (Ebbinghaus et al. 2005), while LU 103793 (another synthetic analogue of dolastatin 15) proceeded to phase II for patients with metastatic breast cancer (Kerbrat et al. 2003) and advanced nonsmall-cell lung cancer (Marks et al. 2003). Dolastatin 10 has been in phase II trials in treatment of patients with advanced nonsmall-cell lung cancer (Krug et al. 2000), hormone-refractory metastatic prostate adenocarcinoma (Vaishampayan et al. 2000), metastatic melanoma (Margolin et al. 2001), advanced colorectal cancer (Saad et al. 2002), recurrent...

Future Trends

And antisense-based products are being evaluated. More than one third of these products aim to treat cancer, particularly melanoma and calorectal cancer, as well as breast and prostate cancer. Of the almost 80 vaccines in development, most aim to prevent treat AIDS or some form of cancer. It is thus likely that several new biopharmaceuticals will gain regulatory approval each year over the foreseeable future.

Liposomes

A key question is whether the liposome can pass through the blood brain barrier (BBB). Unilamellar liposomes with diameters as small as 60 nm are incapable of crossing the BBB. Liposomes have also been used by others to deliver boronated thiouracils to melanoma cells and as a targeting vehicle for BSH through intracerebral administration. An advantage of using liposomes is that the boron species itself does not need to possess tumor-targeting properties. Once the compound is deposited either intracellularly within the tumor cell or interstitially within the tumor by the liposome and has properties that result in cell penetration and binding to subcellular organelles, persistence would be achieved. With respect to brain tumors, the unique restrictive nature of the normal BBB limits penetrability of the CNS, especially for liposomes greater than 60 nm.19c However, in the total scheme of things for all tumors, liposomes may well be an important delivery system for BNCT agents.84

Conclusion

G3139 (Genasense), while initially designed as an anti-Bcl-2-specific drug, clearly has a complex, multimodal mechanism of action that is not completely understood. In this respect, Genasense is similar to virtually every other clinically useful cancer chemotherapeutic agent. Indeed, if Genasense had but a single mechanism of action, it is doubtful that it would be clinically active in a disease as complicated and aggressive as advanced melanoma, a disease that cannot be treated effectively by any of our current therapeutic strategies. These facts alone trump the controversy surrounding the in vitro and in vivo mechanism of action of G3139, which is essentially a question for those primarily interested in basic questions of molecular pharmacology.

Preclinical studies

PEG conjugates of asparaginases from E. coli and Vibrio succinogenes were evaluated for immunogenicity and circulating life in mice and rabbits18. Immunogenicities of the PEG-asparaginases were a small fraction of the native asparaginases. In mice, the circulating half-life of E. coli asparaginase was 5 hours, and E. coli PEG-asparaginase was 3.75 days Vibrio asparaginase half-life was too short to be measured, while that of Vibro PEG-asparaginase was 4.0 days. Ho et al.1 reported a half-life in rabbits of 20 hours for E. coli asparaginase, and 144 hours for PEG-asparaginase. MacEwen and coworkers 19 evaluated the effectiveness of PEG-asparaginase alone or with combination chemotherapy against canine malignant melanoma, and reported antotumor activity.

Colin Goding

The ability of cancer cells to acquire properties of invasiveness and the potential to metastasise is not entirely understood. In the traditional model, the acquisition of cells with metastatic potential is acquired by the accumulation of genetic lesions. Alternatively, metastatic potential could represent a specific epigenetic state that may be inherently unstable properties associated with metastasis could be lost once the metastatic cell has taken up residence in another location. However, while considerable resources have been expended on trying to pinpoint mutations that correlate with metastatic potential, the precise molecular mechanisms underlying any epigenetic model for cancer metastasis have been relatively little explored. In the melanocyte lineage and melanoma the Microphthalmia-associated transcription factor Mitf plays a crucial role in commitment, survival, and differentiation and regulates G1 S transition through up-regulation of the p16INK4a and...

Solid tumors

Melanoma Spitler et al. (1987) conducted a trial of a murine monoclonal antimelanoma antibody-RTA Immunotoxin (XOMAZYME-MEL) in 22 patients with metastatic malignant melanoma. The dose of Immunotoxin administered ranged from 0.01 mg kg daily for 5 days to 1 mg kg daily for 4 days (total dose 3.2-300 mg). Side effects observed in most patients were transient symptoms ascribable to VLS. Symptoms consistent with mild allergic reactions were observed in three patients. The side effects were generally transient and reversible. Encouraging clinical results were observed (1 complete response and 9 mixed response stabilization of the disease), even after a single course of a low dose of Immunotoxin. In addition, localization of antibody and RTA to sites of metastatic disease was demonstrated by immunoperoxidase staining of biopsy specimens. In a study by Gonzalez et al. (1991) 20 patients with metastatic melanoma were treated with escalating doses of XomaZyme-Mel given as a single intravenous...

Clinical results

Five papers have been published on the value of the L-DOPA L-tyrosine ratio as a marker of melanoma progression the main biological and clinical results are summarized in Table 4.3. Figure 4.2 Variation of retention time of l-DOPA as a function of pH of the mobile phase. As the pH increases, the retention time of l-DOPA decreases. NE, norepinephrine E, epinephrine DA, dopamine DHBA, internal standard. Reprinted from Journal of Chromatography B, 696, Letellier S, Garnier JP, Spy J, Bousquet B. Determination of the l-DOPA l-tyrosine ratio in human plasma by highperformance liquid chromatography. Usefulness as a marker in metastatic malignant melanoma, pages 9-17, Copyright 1997, with permission from Elsevier Figure 4.2 Variation of retention time of l-DOPA as a function of pH of the mobile phase. As the pH increases, the retention time of l-DOPA decreases. NE, norepinephrine E, epinephrine DA, dopamine DHBA, internal standard. Reprinted from Journal of Chromatography B, 696, Letellier...

Future directions

A large multi-marker study including LDH, melanoma antigens S100B and melanoma inhibitory activity (MIA) and the L-DOPA L-tyrosine ratio for serological tumor markers has been initiated in Paris in a multi-center approach. The aims of this long-term (10 years) prospective study are to optimize the biological follow-up of melanoma patients and to select the most pertinent marker(s) or combination of markers. Identifying the most appropriate category of patients (AJCC stage or group defined, for example, by a given cut-off) who would benefit from the use of these markers is also of great interest. When analyzing inclusion values in our homogeneous group of 255 patients, the l-DOPA L-tyrosine ratio was, for the first time, significantly higher in stage III (local metastases) Figure 4.3 Plasma l-DOPA l-tyrosine ratio and AJCC disease stage. A total of 255 melanoma patients were included stage I, 54 stage II, 62 stage III, 67 and stage IV, 72 (AJCC staging using Ref. 2). *** Significantly...