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 Overview


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Organspecific Modulation Of Il8 Expression In Melanoma Cells

Human melanoma is an excellent example of a hematogenous malignancy. Melanoma cells secrete a variety of angiogenic molecules, e.g., VEGF, bFGF, and IL-8, and are regulated by complex interactions with keratinocytes in the skin (82). Recent reports from this laboratory show that IL-8 is an important molecule in melanoma growth and progression. Constitutive expression of IL-8 directly correlated with the metastatic potential of the human melanoma cell lines tested. Further, IL-8 induced proliferation, migration, and invasion of endothelial cells, and, hence, neovascularization (83). Several organ-derived cytokines (produced by inflammatory cells) are known to induce expression of IL-8 in normal and transformed cells (83). Since IL-8 expression in melanocytes and melanoma cells can be induced by inflammatory signals, the question of whether specific organ microenvironments could influence the expression of IL-8 was analyzed. Melanoma cells were implanted into the subcutis, the spleen...

Susceptibility To Skin Cancer

Among the residents aged 60 or more years in the BFD-endemic area, the prevalence of skin cancer was 4.8 , 16.5 and 25.6 , respectively, for males whose drinking water had arsenic concentrations of < 300, 300-599 and > 600 Mg l (Tseng et al., 1968). The corresponding figures for females were 0.9 , 6.2 and 11.0 , respectively. However, the status of undernourishment in the development of arsenic-induced skin cancer was not examined in this study. In a recent survey in the BFD-hyperendemic villages, the prevalence of skin cancer was found to increase with the duration of consuming sweet potato in a dose-response relationship (Hsueh et al., 1995). The multivariate-adjusted odds ratios were 5.5 and 8.5, respectively, for those who consumed sweet potato for 10-19 and > 20 years compared with those that had a consumption duration of < 10 years. In another nested case-control study in BFD-hyperendemic villages, the incidence of arsenic-induced skin cancer was found to increase with...

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....

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...


BMS-345541 (7) (IKK-2 IC50 300 nM, IKK-1 IC50 4,000 nM) demonstrated dose-dependent inhibition of the growth of three different human melanoma cell lines when inoculated into nude mice 35 . Administration of this compound also resulted in a dose-dependent decrease in the incorporation of 32P into GST-IkBa in one of the melanoma cell lines, consistent with IKK-2 inhibition in vitro, as well as a dose-dependent increase in apoptosis in melanoma cells.

Skin Cancer

Skin cancer is the most commonly occurring type of cancer in the United States. Experts estimate that 40 to 50 percent of Americans who live to age 65 will eventually develop some form of skin cancer. The risk is highest for people who have red or blond hair, light-colored eyes, and fair skin that freckles easily. The two most common forms of skin cancer are basal cell carcinoma, which accounts for more than 90 percent of all skin cancers, and squamous cell carcinoma. Basal cell carcinoma is a slow-growing cancer, found in the base of the outer layer of skin, that rarely spreads to other parts of the body. Squamous cell carcinoma, which affects cells in the surface of the skin, also spreads infrequently, although it does so much more often than basal cell carcinoma. A less common type of skin cancer, malignant melanoma, is the most serious form of skin cancer. It spreads quickly and can be fatal. The number of people with melanoma has more than doubled in the United States since about...

Organometallic GSK3 inhibitors

In an unrelated study, the activities of a pair of ruthenium 19 and osmium 20 congeners of 18 were compared 93 . Both analogs were evaluated in a variety of biochemical and cell assays and had essentially indistinguishable properties. Both 19 and 20 were highly active at GSK-3b (IC50 1.4 and 0.6 nM, respectively), and both induced strong and essentially identical apoptotic effects in 1205 Lu melanoma cells. This effect is thought to be attributable to GSK-3 inhibition that produces p53-induced apoptosis. The equivalence of these ruthenium and osmium complexes in a cytotoxicity assay using 1205 Lu cells is noteworthy, as such exchange of one metal with its higher periodic table congener is not normally tolerated in many classes of cytotoxics.

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

Tumor Specific Antigens

This category of tumor antigens, which represents non-mutated gene products that are not processed and presented on normal adult tissues, is predominantly comprised of members of the cancer testis (C T) family of genes (Table 2). The expression of C T gene products is limited in adult tissues to the normal testis, which lacks expression of HLA class I and class II molecules. The prototype for this family, MAGE-1, represents the first antigen to be identified as a target of human tumor reactive T cells, and was cloned by transfecting an autologous tumor cell line that appeared to have lost antigen expression with a cosmid library containing genomic DNA from antigen positive tumor cells (1). The cancer testis genes have been clustered into 10 families, 6 of which have been mapped to the X chromosome (3 8), and subsequent studies have lead to the identification of T cell epitopes expressed on multiple products derived from these gene families. The MAGE gene family includes 17 members,...

Association with other diseases

As well as these haematological disorders, specific infiltrates of mycosis fungoides can be observed in benign and malignant skin tumours such as melanocytic naevi, malignant melanoma and seborrhoeic keratoses among others (Fig. 2.15) 35 . In these cases, the association of the two diseases represents an example of 'collision tumours'.

Distribution in Normal Tissues

Distributions of pO2 values in various normal human tissues have been described in detail (49-53). The normal tissues were subcutaneous tissues surrounding tumors for ear, nose, and throat (ENT), sarcoma, and melanoma patients, normal brain for gliomas, and vaginal mucosa for cervix tumors (49-55). As expected, there is a scattering of the individual pO2 values in normal tissues between 1 mmHg and values typical for arterial blood (80-100 mmHg). Whatever the normal tissue, median pO2 ranged from 15 to 70 mmHg. For example, in patients with head and neck tumors, median pO2was 52 mmHg in the Institut Gustave-Roussy (IGR) experience (mean 54 mmHg) (52) and mean pO2 was 57 mmHg at Stanford (55).

Hla Class Ii Restricted Antigens

From HLA-DRpi*0401 positive melanoma patients with the peptide that appeared be most effective at stimulating T cells from immunized mice, NY-ESO-1 116-135, resulted in the generation of T cells that recognized HLA-DR4 positive tumor cells and target cells pulsed with the NY-ESO-1 protein.

Generation Of Tumor Antigen Epitopes

Translated in the third alternative open reading frame (AORF), and a T cell epitope that was recognized by an HLA-A11 restricted, tumor reactive TIL was present within this AORF. A melanoma that expressed a p16INK4a transcript containing a 2 base pair exon 2 deletion that resulted in the translation of the this AORF was also recognized by the HLA-A11 restricted TIL. Frame-shifted CDKN2A products are expressed at high frequencies in certain tumor types (83, 84), and thus this represents a highly shared mutated epitope that could be utilized as a target for immunotherapy in patients bearing certain cancers. Expression of the immunoproteasome, which has a distinct peptide cleavage specificity from the proteasome and which can be induced in a variety of cells by stimulation with interferon gamma (IFN-y), may also affect the processing of certain T cell epitopes. The treatment of tumor cells with IFN-y nearly eliminated the ability of those cells to stimulate T cells that recognize...

Influence Of T Cell Tolerance On Tumor Antigen Recognition

Many of the T cell epitopes that have been identified from self antigens such as the MDAs bind to HLA class I gene products with relatively low affinities, and observations made in mouse as well as human studies indicating that the repertoire of T cells that is available for recognition of these antigens is at least partially influenced by tolerance mechanisms may be relevant to this finding. In one study, HLA-A2 transgenic mice that either expressed the normal mouse tyrosinase molecule or that failed to express this protein as a result of a radiation induced deletion of sequences that encoded this gene were immunized with the mouse analog of the tyr 369-377 peptide FMDGTMSQV (98). The results indicated that the precursor frequency of high affinity T cells reactive with the tyr 369-377 epitope was significantly reduced in normal mice relative the to knock-out mice. In a recent human study, an HLA-A24 restricted T cell epitope was identified from the OA1 melanocyte differentiation...

The Most Recent Past And The Future

New herpesviruses continue to be discovered, whilst only HHV1 and 2 are significantly inhibited by the existing drugs. Threats of bioterroism will lead to evaluation of drugs against smallpox such as cidofovir and against viruses which cause haemorrhagic fevers such as Lassa and Ebola. Influenza has recently been added to the list of potential bioterrorist viruses.

Essential Components Of An Effective Taspecific T Cellbased Immune Response

Both the SEREX, T-cell-based and reverse immunology approaches have identified a variety of tumor antigens (TA), which can be broadly classified as tumor antigens that are capable of being recognized by the immunocompetent host (a) cancer-germ line antigens such as MAGE 1 or 3, BAGE, GAGE and many others that are silent in normal tissues, with the exception of germ cells in the testes and ovaries but expressed in a variety of histologically distinct tumors (3-5) (b) differentiation-specific antigens exemplified by melanoma- and melanocyte-associated tyrosinase, MART-1 Melan-A or gp100 (3-5) and (c) unique antigens generated by point mutations in ubiquitously expressed genes, which regulate key cellular functions, such as MUM-1, CDK4, FLICE or b-catenin (3-5) (d) overexpressed antigens, such as p53, MDM2, CEA, which are components of normal cells but in tumor cells are greatly increased in expression (35,25). Despite the fact that the majority of the known TA, with the...

Integrin Linked Kinase

Integrin-linked kinase (ILK) is an ubiquitously expressed serine threonine kinase that binds to the cytoplasmic domain of the pi integrin subunit.98 It is involved in the regulation of cell survival and plays a role in cancer, with its upregula-tion identified in cancers of the colon, breast, prostate, and lung, and in melanoma.28,35-38 ILK is upregulated, often in a stage- and grade-dependent manner, and is associated with metastases.28 ILK is a central structural and signaling protein that serves as a link between the extracellular matrix and

Mechanisms For Protection Of Immune Cells And Prevention Of Tumor Escape

Attention must also be focused on immunized patients' tumor cells susceptibility to immune recognition and destruction. As discussed above, defects in HLA class I antigen expression have been convincingly documented in melanoma large number of malignant lesions of different histotype (20). Although not conclusive, the available evidence suggests the clinical relevance of these defects, since they are associated with a poor course of the disease in several malignancies, are present with increased frequency in malignant lesions of patients treated with T cell-based immunotherapy (20). These findings have been interpreted to indicate the outgrowth of malignant cells which have acquired the ability to escape T cell

Organdependent Expression Of Basic Fibroblast Growth Factor By Tumor Cells

Recent clinical observations have noted antiangiogenic effects in vascular tumors, including hemangioma (65-70), Kaposi's sarcoma (71-74), melanoma (75), basal cell and squamous cell carcinoma (76), and bladder carcinoma (77), using recombinant interferons. These tumors have also been documented as producing high levels of bFGF, often detectable in the urine or serum of these patients (78,79). These findings, along with in vivo observations, prompted investigation of whether IFNs could modulate the expression of the angiogenic molecule, bFGF. The authors found that IFN-a and IFN-p, but not IFN-y, downregulated the expression of bFGF mRNA and protein in HRCC, as well as in human bladder, prostate, colon, and breast carcinoma cells (80). The inhibitory effect of IFN-a and -P on bFGF expression was cell-density dependent and independent of the antiproliferative effects of IFNs (80,81). The authors recently confirmed that IFN can inhibit bFGF production in an in vivo model system....

Tumor Escape And Future Approaches To Cancer Immunotherapy

Extensive immunization trials are on-going worldwide in patients with breast, colon, renal cell, ovarian and prostate carcinomas as well as melanoma and other malignancies. These clinical trials, largely initiated in patients with advanced metastatic disease, have been able to induce clinical responses in not more than 20 of patients. They are unlikely to yield the desired results, if only a proportion of the immunization-induced, TA-specific effector cells survive in vivo. Moreover, if a proportion of specific T cells or DC are preferentially killed, and if the level of apoptosis exceeds that of effector cell influx into the tumor or their generation within the secondary lymphoid sites, the immunization strategies (as currently applied) may prove ineffective. Likewise, it may be counterproductive to generate TA-specific effector cells in a situation where the tumor is resistant to that type of immune cell, i.e., poised to escape specific immune interventions. To avoid additional...

Signaling Events Associated with Adenovirus Internalization

While further research is needed to fully characterize Ad cell entry mechanisms, the identification of specific signaling molecules involved in adenovirus cell entry may allow improvements in Ad-mediated gene delivery to cells which lack CAR and or av integrins. For example, ligation of certain growth factor receptors (i.e., epithelial growth factor (EGF)) or cytokines (i.e., tumor necrosis factor alpha (TNFa)) results in activation of remarkably similar signaling pathways as those induced by integrin clustering 101-103 . Li et al. recently investigated whether activation of growth factor receptors could circumvent the need for av integrins CAR in adenovirus-mediated gene delivery 104 , They generated a bifunctional antibody that recognizes the penton base RGD motif (DAV-1) as well as one of several different cytokine or growth factor receptors. Ad vectors complexed with these bifunctional molecules significantly increased PI3K activation in host cells and improved gene delivery to...

Modulation Of Angiogenesis By Host Lymphoid Cells

The regulation of physiologic angiogenesis by lymphoid cells is well established. Angiogenesis is influenced by cytokines released from mast cells, T-lymphocytes, and macrophages in the tumor microenvironment (88-95). Mast cells have been associated with disease progression in infantile cutaneous hemangiomas (96). In fact, the presence of elevated numbers of mast cells has been used to distinguish hemangiomas from vascular malformations (97). Lymphoid-mediated angiogenesis has been recognized in cutaneous melanoma. Increased vascularity at the vertical base of human melanoma is associated with poor prognosis (98). A local inflammatory reaction is often associated with invasive cutaneous melanoma. An intense inflammatory reaction is often associated with increased risk of metastasis, suggesting that inflammatory-associated angiogenesis may contribute to melanoma dissemination (99,100). This laboratory has shown an important role for host-infiltrating leukocytes and their products in...

FGF1 and FGF2 in Tumor Development

Extensive studies on the expression of FGF-1 and FGF-2 in tumor biopsies in vivo together with functional studies on tumor cell proliferation in vitro, provided a plethora of evidence for the involvement of FGF-1 and FGF-2 in tumor development. In some cases, expression of FGF-1 or FGF-2 correlated with malignancy, and interference with the activities of FGF-1 or FGF-2 diminished tumor growth and cell transformation (15). FGF-1 and FGF-2 were significantly upregulated in human gliomas, proportional with the degree of malignancy (15). Furthermore, the malignant phenotype of glioblas-toma cell lines could be inhibited by FGF-2-specific antibodies, indicating that FGF-2 utilized an autocrine pathway to promote tumor progression (16). FGF-2 and sometimes FGF-1 are constitutively expressed at high levels in melanomas, but not in normal melanocytes (8). Proliferation and growth in soft agar was inhibited by antisense oligonucleotides to FGF-2 or FGFR-1 in melanoma cell line, indicating that...

FGF Receptors and Tumorigenesis

Similar to the FGF ligands, expression of FGFRs is significantly upregulated in a variety of cancer types. For example, the genes for FGFR-1 and -2 were found to be amplified and overexpressed in a subset of breast cancers. In these cases, amplification of FGFR-2 significantly correlated with amplification of the gene for c-myc amplification of FGFR-1 correlated with the amplification of the genes for FGF-3 and FGF-4 (50). The gene for FGFR-2 was found to be amplified in stomach cancer, in which it was isolated as K-sam (40). FGFR-1 expression was found to be upregulated in glioblastoma FGFR-2 was present in white matter and low-grade astrocytomas, but absent in glioblas-toma. Indeed, during progression to the most malignant phenotype of glioblastoma, a gradual shift from FGFR-2 to FGFR-1, with two or three Ig domains, was observed (51). Expression of both FGFR-1 and FGFR-2 was found to be upregulated in gliomas and meningiomas (19). Inhibition of FGFR-1 expression by antisense...

Inhibition of FGF Activity

Another approach to interfere with tumor growth is the ligand-specific targeting of toxins to tumor cells expressing FGFRs. For example, a fusion protein consisting of FGF-2 and saporin, a cell toxin isolated from the plant saponaria, was specifically targeted to FGFRs, and exhibited antitumor activity in vitro and in vivo (112). Recombinant versions of these fusion proteins expressed in Escherichia coli inhibited growth of B16-F10 melanoma cell lines in vitro, and retarded tumor growth and metastasis in vivo (113). Alternatively, fusion of FGF-1 to Pseudomonas exotoxin A resulted in specific cytotoxicity to a variety of tumor cell lines expressing FGFRs, including those of prostate, colon, or breast carcinoma (114). Systemic application in athymic mice grafted with several different tumor cell lines slowed tumor growth, but did not induce complete regression. Probably, the exotoxin attacked the tumor mass, rather than the tumor endothelium (114). Pseudomonas exotoxin FGF-1 fusion...

Killing Mechanisms Used In Host Responses To Syngeneic Tumors

It is now clear that killer lymphocytes can use several mechanisms to destroy aberrant self-cells including tumor cells. The most vigorous of these are based on the perforin and Fas pathways, with perhaps a lesser contribution of TNF and related pathways (54). One of the first comprehensive looks at the role of perforin in rejection of syngeneic tumors was carried out by van den Broek et al (55, 56). They looked at rejection of a wide range of lymphoid and non-lymphoid tumors in perforin knockout mice, compared to normal controls. The results varied widely, with no obvious relation to tumor type. A melanoma was equally lethal in mice with or without perforin. A fibrosarcoma grew about ten times more readily in perforin-deficient mice, although both the knockout mice and normal controls developed stable tumors. Both mice rapidly rejected a modified adenovirus-induced tumor. In general, among lymphoid tumors, perforin deficient mice were 100-1000 times more susceptible to some, and...

Cancer Vaccines That Elicit

In humans, extensive work has been done to define peptides associated with malignant melanoma such as MART-1 and gp100 (reviewed in 82 87), and clinical trials have been underway for the past several years. Clinical trials using a modified gp100 peptide administered together with IL-2 yielded promising results. Objective tumor regressions were obtained in 42 percent of HLA-A2-positive patients with advanced melanoma (88). IL-2 appeared to promote sequestration of responding CTL at the tumor site (89). In an unrelated trial a selected peptide from MART-1 was shown to induce significant CTL responses in melanoma patients, which correlated with a prolonged time to relapse (90). Vaccine trials with peptides representing other cancers including breast (91), cervical (92), and pancreatic (93), are underway, and have given broadly similar results where reported. As with the melanoma trials, these are all Phase I II studies, restricted to patients with advanced cancer who have failed...

Betacarotene Primary Prevention Trials

The Skin Cancer Prevention Study randomized 1,805 men and women with a history of skin cancer to 50 mg of beta-carotene daily or placebo.52 After a median treatment period of 4.3 years and median follow-up of 8.2 years, there was no significant reduction in CVD mortality (RR 1.15 95 CI, 0.81-1.63), cancer mortality (RR 0.86 95 CI, 0.56-1.32), or total mortality (RR 1.05 95 CI, 0.83-1.32) associated with beta-carotene supplementation. Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) Skin Cancer 1,805 men and women with history of skin cancer United States cIn Skin Cancer Prevention Study, treatment was for 4.3 years and follow-up was for 8.2 years.

Inhibitors of Apoptosis Proteins

The IAPs, first discovered in baculoviruses and then in insects and Drosophila, inhibit activated caspases by directly binding to the active enzymes.85 These proteins contain one or more baculovirus inhibitors of apoptosis repeat domains, which are responsible for the caspase inhibitory activity.8 6 To date, eight mammalian IAPs have been identified they include X-linked IAP (XIAP), c-IAP1, c-IAP2, Melanoma IAP (ML-IAP) Livin, IAP-like protein-2 (ILP-2), neuronal apoptosis-inhibitory protein (NAIP), Bruce Apollon, and Survivin. In mammals, caspase-3, -7, and -9 are inhibited by IAPs.)3 ) There are reports suggesting aberrant expression of IAPs in many cancer tissues. For example, cIAP1

Susceptibility To Transitional Cell Carcinoma

Blackfoot Disease and Arsenic-induced Skin Cancer In a cohort study on urinary bladder cancer, mainly transitional cell carcinoma (TCC), in the BFD-endemic area, an increased risk was observed among patients affected with BFD as compared with the unaffected (Chiou et al., 1995). The odds ratio of developing urinary bladder cancer was around four-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In our most recent cohort study on TCC in the BFD-endemic and non-endemic areas, an increased risk of developing TCC was observed among patients affected with skin cancer than the unaffected. The odds ratio was around five-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In a nested case-control study in the BFD-endemic area, an increased cancer risk was significantly associated with the elevated frequency of chromosome-type aberrations in peripheral lymphocytes (Liou et al., 1999). Both skin cancer and transitional cell...

Circulating TSP1 Can Slow Tumor Growth and Produce Concomitant Tumor Immunity

Circulating levels of TSP-1, whether produced endogenously by tumors releasing high amounts of the protein, or exogenously by daily injections of purified protein, render mice unable to mount an angiogenic response, and also halt the growth of experimental lung metastases (19). When the human fibrosarcoma HT1080, producing high levels of TSP-1, is grown subcutaneously in a nude mouse, the animal develops a high circulating level of human TSP-1 that can reach 10 g mL in plasma. This circulating TSP-1 is able to dramatically reduce the growth of B16 melanoma lung metastases seeded by tail vein injection. Inhibition is probably caused by the inhibition of angiogenesis, because animals treated with TSP-1 become antiangiogenic, in that they are unable to mount a corneal angiogenic response to bFGF TSP-1 has no effect on the in vitro growth rate or cloning efficiency of the melanoma cells forming the metastases and the inhibition of the growth of metastases in vivo is reversible if TSP-1...

Use Of Other Apoptosisregulated Proteins And Events In Detection Of Apoptosis

The bcl-2 family of proteins represent both repressors (bcl-2, bcl-xl) and inducers (bax, bak) of apoptosis. The ratio of bcl-2 bax expression as determined by immunohistochemical evaluation in pediatric acute lymphoblastic leukemia (22) and in nonlactating human mammary gland epithelium (23) may determine whether or not a cell becomes apoptotic. Levels of bcl-2 and bcl-xl expression detected by immunohistochemistry appear to increase with the progression of malignant melanoma consistent with the idea that there is an increased malignant potential caused by inhibition of apoptosis by an increase in expression of apoptosis repressors (24). However, bcl-2 overexpression has been correlated with a lower risk of metastases and death in patients with infiltrating breast carcinoma (25) and has also been shown to have no prognostic significance with human colon carcinoma (26) so the relationship between bcl-2 and cancer progression is not clear.

Carcinogenic Interactions For Ingested Arsenic

Methylation capacity has been hypothesized to play a role in susceptibility to arsenic-induced carcinogenicity. Hsueh et al. (1997) classified subjects from a Taiwanese study according to the percent of arsenic excreted as monomethyl arsonic acid (MMA) in urine and also by cumulative arsenic exposure. These authors found that the multivariate adjusted odds ratios for skin cancer differed in these four groups. Within the low cumulative arsenic exposure group, those with a higher percentage of urinary MMA showed a relative risk of 3.0 compared to those with a lower percentage (< 26.7 ). Among those with a low excretion of MMA, a higher cumulative arsenic exposure was associated with an 8-fold increased risk of skin cancer. However, when comparing the highly exposed, high MMA excreters to those with low exposure and low MMA excretion, the OR was 24. These findings suggest that methylation capacity could substantially alter the additive impact of arsenic exposure, i.e., the number of...

Tumor Invasion and Metastasis

The first studies with MMP inhibitors in cancer models examined their ability to block organ colonization or experimental metastasis. Marked inhibition of colonization was demonstrated for both TIMP-1 and the hydroxamate SC44463 (1 Searle) in mice inoculated with B16 murine melanoma cells (95,96). Similarly, TIMP-2 was shown to inhibit colonization by 4R transformed rat fibroblasts (97). These models only examine one discreet part of the the multistep process of tumour invasion and spread. More recently, MMP inhibitors have been tested in more complex and more clinically relevant cancer models.

Spontaneous tumor immunity

It has long been a matter of debate whether tumors are spontaneously immunogenic in patients. With the availability of sensitive methods, spontaneously occurring T cells directed against tumor associated antigens (TAA) can be detected in cancer patients. There is increasing evidence that CD8+ T cells directed against TAA spontaneously occur in various malignancies including melanoma, adenocarcinomas, and leukemias (reviewed in 13). Mechanisms leading to spontaneous induction of specific T cell responses are not well understood. Whether circulating TAA-specific T cells are able to kill tumor cells in vivo and how they influence the clinical course of disease has remained largely unclear. Further studies are necessary for a better understanding of the role of spontaneous T cell responses against TAA.

Antioxidant nutrients

Selenium supplementation has been reported to have a variety of positive effects on the cardiovascular system, the immune system, and on general health, not all of which necessarily reflect its antioxidant role.47 However, it is reasonable to propose that adequate selenium status is required to minimise the risk of cancer because maintenance of cellular redox balance is probably crucial to the prevention of free-radical mediated DNA damage. The design of epidemiological studies to test this hypothesis has been complicated by the difficulty of assessing accurately the exposure of individuals to dietary selenium, but there is evidence of an inverse relationship between risk of cancer and dietary intake of selenium at the population level.48 Prospective studies in which the incidence of cancer has been correlated with selenium status assessed by analysis of toenails have provided evidence of protective effects against a variety of cancers, but such studies have usually been relatively...

Ethanol And Vascular Smooth Muscle Cell Migration

The accumulation of SMC in the intima of arteries is one of the most prominent features of the atherosclerotic plaque and of the intimal hyperplastic lesions which cause restenosis following angioplasty 35,36 , It is increasingly recognized that migration of SMC from the media is a key event in progressive intimal thickening leading to atherosclerosis and restenosis 35-37 , Consequently, there has been extensive interest in defining both positive and negative regulators of this process and many factors have been identified that may play a role. While ethanol has been shown in vitro to differentially influence the migration of neuronal cells 38 and melanoma cells 39 , its effect on SMC migration has not been defined until recently.

Monitoring vaccination studies

Development is the correlation of clinical efficacy with T cell responses as surrogate markers. There is increasing evidence now from various clinical cancer vaccination trials for a relation between the detection of vaccine-induced T cells by cytokine-based assays and clinical responses (reviewed in 14). Standardization and validation of T cell assays to monitor the induction of specific T cells responses is crucial to reliable monitoring of clinical trials. Several expert workshops have been performed within the EORTC melanoma group and the International Society of Biological Therapy of Cancer (ISBTC) on T cell assay methodology and standardization (15, 16). The simultaneous use of two ex vivo T cell assays including a functional assay for T cell monitoring has been proposed (16). Controls for the quality of the samples as well as for the accuracy and reproducibility of the assay are a prerequiste for clinical T cell monitoring as outlined above.

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...

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...

Induction of Immunity by Activated DCs

In an attempt to induce protective anti-tumor immunity, the melanoma antigen tyrosinase-related protein 2 (TRP2) was coupled to anti-DEC antibodies and injected into mice. Simultaneously, a DC-activating stimulus by injection of CpG was administered. After two consecutive injections of these anti-DEC-tumor antigen conjugates, mice were challenged for tumor growth by intravenous injection of the melanoma cell line B16. After two weeks, metastases in the lungs of the mice were counted. Our results clearly show that mice were protected from tumor growth after two immunizations with antibody-tumor antigen conjugates when injected together with an activating stimulus, i.e., CpG (38). This protection was lost when CpG was omitted from the immunization procedure, indicating that activation of the DC is mandatory for effective induction of an immune response.

PNS of the Peripheral Nervous System

Seronegative sensory-motor neuropathy with additional features such as involvement of the face and trunk, sensory ataxia, CNS signs, and inflammatory changes in the CSF have been reported among patients with breast cancer 116 . In such distinct patient populations, new target antigens will probably be identified in the future. Antibodies to gangliosides were described in patients with progressive neuropathy and malignant melanoma 117 and SCLC 118 . In the latter case, the SCLC expressed the ganglioside antigens, and there was a clonal expansion of VS 1 positive T cells in peripheral blood as well as in the tumor. In addition, the neurological symptoms stabilized after tumor therapy. Gangliosides are, however, not a frequent target in paraneoplastic neuropathy 119 .

Ist In A Number Of Experimental Settings

Most pertinent to readers of this book, IST has been used to study CTLs directed against cancer antigens. Using a mouse tumor model, Haanen et al. used IST to show that tumor rejection was associated with the infiltration of tumor specific T cells. In human melanoma, T cells specific for the tumor antigen survivin were readily detected in tissue sections from the primary tumor and a sentinel lymph node isolated from a melanoma patient (6). Similarly, in tissues from a breast cancer patient, survivin specific T cells were readily detectable in situ. Importantly, these cells were shown to have functional cytotoxic activity when assayed ex vivo (6).

Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Triciribine (API-2, TCN, 28a) is a tricyclic nucleoside first reported in 1980 51 . While 28a and the corresponding 5-phosphate derivative (triciribine phosphate, TCN-P, 28b) have demonstrated antitumor activity and progressed to clinical evaluation for the treatment of several advanced solid tumors, severe side effects (e.g. hepatotoxicity and hyperglycemia) related to dosing levels ultimately limited their use 52-59 . More recently, screening of the National Cancer Institute Diversity Set identified 28a as a highly selective inhibitor of AKT, wherein cell growth was suppressed at a concentration of 50 nM 60 . While it is known that 28a blocks the AKT pathway, the mechanism by which it prevents AKT activation has not been established. Additional preclinical findings report that 28a, at a dose of 5 p.M, effectively and selectively induced apoptosis and cell growth arrest in tumor cells in which AKT was aberrantly expressed or activated, while cancer cells without this trait were not...

Ist To Monitor T Cell Directed Vaccine Trials In Cancer Patients

Schrama et al. characterized the inoculation site of dendritic cell (DC) vaccination in patients with melanoma. They determined that antigen pulsed DC, but not unpulsed DC recruited and induced the local expansion of melanoma specific T cells at the inoculation site. They used MHC-multimers loaded with melanoma antigens MART, MAGE3, and gp100 and stained skin biopsies from vaccinated patients to demonstrate the specificity of the recruited and expanded T cells at the inoculation site. As discussed above, T cells specific for the tumor antigen survivin taken from melanoma and breast cancer tumors were shown to be cytolytic ex vivo (6). In contrast, recent studies of T cells specific for the MART tumor epitope showed that the tumor specific T cells had effector function in circulating blood but were functionally tolerant in tumor lesions (21). Findings such as these demonstrate that the functional status of T cells in blood does not always reflect the functional status in tissues and...

Angiostatin and Endostatin

Recently, O'Reilly et al. (115) identified another antiangiogenic protein isolated from a hemangioendothelioma and called endostatin. Endostatin is a smaller protein than angiostatin, and is a 20-kDA C-terminal fragment of collagen XVIII. Endostatin has been shown to inhibit the growth of the LLC when administered at doses of 10 or 20 mg kg daily by intraperitoneal injection. Similar results were found in animals bearing the T241 fibrosarcoma, the B16 melanoma, and the EOMA hemangioendothelioma.

Data Interpretation

Monoclonal or oligoclonal TCR VB families may occur in EBV or CMV-specific T-cell responses and reflect the immunological memory of previous encounters with antigens (19, 20). Some alterations can also be identified in CD4+ T-cells, presumably reacting to common infectious agents, e.g. CMV (21). Due to structural constraints of the TCR interaction with its nominal MHC peptide ligand, some T-cell responses are characterized by a common usage of a TCR VB family, but not with a common CDR3 motif. For instance, the HLA-A2 restricted CD8+ T-cell response targeting the influenza matrix peptide Ml (aa 58-66) shows a preferential usage of the TCR VB17 family (22) which is polyclonal in nature. Other, preferential usage of certain TCR variable families may also be present in the human population. This is difficult to assess, since these studies depend either on the generation of bona fide T-cell clones directed against a single MHC peptide complex, or alternatively on...

Conclusions 61 Prognosis

Contradictory results Retrospective studies on microvessel density in primary colorectal and malignant melanoma of the skin gave contradictory results on the prognostic significance of such a marker. Therefore, more homogeneous groups of patients need to be evaluated prior to drawing any definitive conclusions.

Sunburn and Protecting Your Skin from the

Too much exposure to ultraviolet rays from the sun, sunlamps, or tanning beds produces sunburn. The most common symptom of sunburn is red, swollen, and painful skin that can blister. If the sunburn is severe and covers a large portion of your body, you may also experience chills, fever, nausea, and vomiting. Repeated sun exposure also can produce harmful long-term effects, including wrinkling, premature aging of the skin, and skin cancer (see page 428). The most serious type of skin cancer, malignant melanoma (see page 428), is often fatal. People who are most likely to be sunburned and who are most at risk for sun-induced skin cancer are those with fair skin, blue eyes, and red or blond hair, although anyone who spends time outdoors is at risk. The more sun exposure you receive, the more your skin is damaged. Certain medications such as the antibiotic tetracycline, some diuretics (water pills), some tranquilizers, birth control pills, and over-the-counter antihistamines make the skin...

Phase Iii Trial Design

The adjuvant setting may ultimately be where Als provide the greatest benefit however, identifying the efficacy of the AI in this setting w ill require a commitment of patient resources, time, and money. The efficacy of adjuvant therapy, following complete surgical resection of a tumor, has been proven for breast cancer, colon cancer, and melanoma. The rationale for adjuvant therapy is to eradicate microscopic disease. In designing a clinical trial in the adjuvant setting for a particular disease, it is important to understand the natural history of patients rendered free of disease by surgery, radiation, and or chemotherapy. As an example, response rates of 85-95 , including 50-60 CRs, can be achieved with combination chemotherapy in limited-stage, small-cell lung cancer (50). Unfortunately, the median survival remains between 12-16 mo. Patients attaining a CR to standard cytotoxic chemotherapy could be considered for a trial randomizing patients between an AI or placebo. The number...

Problems during pregnancy

Malignancies may be affected by the different hormonal profile of pregnancy and its effects on the tissues this may make certain tumours more aggressive (e.g. breast cancer, melanoma). Some maternal malignancies may metastasise to the fetus or placenta (e.g. melanoma), although in general this is rare.

Direct Assessment Of Tcell Responses Against Tumorassociated Antigens Utilizing A Qrtpcr Assay

An immunization monitoring assay that could detect CTL (cytotoxic T lymphocytes) reactivity directly from peripheral blood, rather than after prolonged in vitro proliferation, was developed in the context of a clinical trial in which melanoma patients were vaccinated with modified peptide derivatives from the gp100 tumor antigen (17). PBMC were obtained by leukapheresis from patients before and after two cycles of peptide vaccination. Initial optimization experiments were conducted by simply exposing bulk PBMC ex vivo to the immunizing and native peptides or melanoma tumor cells. No prior in vitro sensitization or culturing of the PBMC was performed, nor were exogenous cytokines added to the cells. Because of the low overall frequency of tumor reactive CTL in bulk PBMC after immunization, changes in cytokine release after peptide elicitation were typically below the sensitivity of standard antibody detection (ELISA) assays. Therefore, real-time qRT-PCR for cytokine gene expression was...

Application Of Qrtpcr In Immune Monitoring Of Patients

The original application of qRT-PCR for the measurement of specific T cell responses to tumor antigens was described in a pilot study examining patients immunized with peptides derived from a melanoma tumor antigen (17). This study demonstrated tumor specific CTL directly in the peripheral blood of patients who had undergone immunization and further validated the An important additional application of qRT-PCR is in the monitoring of in vivo tumors during therapy. Previously, macroscopic, microscopic and molecular changes in targeted tumor sites required resection and analysis. This approach would therefore eliminate the ability to sequentially follow an individual lesion prospectively during treatment. We have developed techniques to perform serial fine needle aspirates (FNA) of accessible tumor sites before and during immunotherapy. This proved to be atraumatic to the tumor, while leaving it in situ for clinical observation and immunologic monitoring. Initially these FNAs were...

Genetic Polymorphisms And Cancer Heterogeneity

Genetic polymorphism is the genesis of the diversity of human beings. Polymorphisms are particularly frequent in genes associated with immune function possibly resulting from an evolutionary adaptation of the organism facing an ever changing environment (16). Although, several genes associated with immune function may bear relevance to tumor host interaction(s) (17), most studies attempting to link human polymorphism to immune responsiveness have been focused on the associations between the Human Leukocyte Antigen (HLA) complex and disease occurrence or response to therapy. However, an extensive analysis of patients with metastatic melanoma treated with systemic interleukin-2 administration

Doselimiting Toxicities And Determination Of Maximumtolerated Dose

DLTs were reported for three of 32 prostate cancer patients, two of 21 cervical cancer patients, and five of 68 solid tumor patients. Excepting one report of hemoptysis (grade 1), which occurred in a patient with NSCLC with a history of similar episodes, all were neurological in nature. DLTs involving complaints of gait and coordination disturbances, memory impairment, increased anxiety, and emotional lability were observed in three prostate cancer patients at two dose levels, 70.6 (two patients) and 105.9 (one patient) mg m2. In two cases, the DLTs presented within the first 3 wk of treatment in one case they were delayed and reported after the 2-wk rest period. Two cervical cancer patients experienced DLTs following treatment at 71 mg m2 for 4 wk these consisted of gait disturbance as well as dizziness and nystagmus. In the solidtumor study administering TNP-470 every MWF, a single DLT (grade 1 unsteadiness) was reported in a patient with melanoma after 102 d of treatment at 32.4 mg...

The Impact Of Genetic Variation And Cancer Heterogeneity On Immune Responsiveness

As we previously discussed, genetic background may influence immune responsiveness. However, the genetic background of patients has not been extensively scrutinized as a predictor of immune responsiveness (16). Obvious genetic markers that may affect immune responsiveness are the HLA complex that codes for molecules responsible for antigen presentation to T cells (51). However, correlates between HLA phenotype and treatment outcome or survival failed to provide conclusive evidence that individual variability in antigen presentation may determine immune responsiveness in the context of anti-cancer immune therapy (18 52 53). Others have pointed to other polymorphisms as harbingers of immune responsiveness. For instance polymorphisms of the IL-10 gene appears to be responsible for differential levels of expression of this cytokine in various conditions. Interestingly, individuals with a phenotype associated with low IL-2 production appear to bear an increased incidence of melanoma and...

Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare, fatal autosomal recessive disorder that affects about 1 in 250,000 people worldwide. The major clinical feature of XP is the early onset of skin cancers that originate from the outermost (squamous) or innermost (basal) cells of the epithelium of the skin. Numerous pigment spots, which are often the sites of skin cancers, form in XP individuals. Other cancers associated with XP include malignant melanoma, keratoacanthomas, sarcomas, and adenocarcinomas. XP patients are extremely sensitive to light, develop lesions of the skin, eyes, and tongue, usually have neurological abnormalities, and demonstrate an impaired ability to learn. They seldom survive past 20 years of age.

Dynamic Monitoring Of Anticancer Immune Responses

Determine the occurrence of immune-induced cancer regression in humans (56). The introduction of gene profiling arrays is particularly suited to circumstances when little is known about a biological event to conceive plausible hypotheses. This is clearly the case of immune-mediate cancer rejection. We tested whether global transcript analysis could segregate lesions likely to respond to immunotherapy by obtaining FNA from subcutaneous melanoma metastases prior to immunotherapy (49). This work was based on a previous observation suggesting that cutaneous melanomas can be segregated into two distinct taxonomies based on global transcript analysis (57). Such observation stimulated the question of whether two disease pathologically defined as melanomas had a different biology and consequently, perhaps, different predisposition to respond to immune therapy. However, the original observation was based on the analysis of cell lines or tissue preparations that has been collected a long time...

Are Alterations In The Apoptotic Machinery Determinants Of Drug Sensitivity

Moving further downstream, silencing of APAF-1 has been reported in a large fraction of melanoma cell lines and clinical samples (280). Consistent with prior observations in Apaf -1- - murine fibroblasts and thymocytes (281), the Apaf-1-deficient melanoma cells were reportedly resistant to doxorubicin-induced apoptosis (280). Although the authors concluded that they had identified a major mechanism of drug resistance in melanoma, subsequent observations have called this conclusion into question. In particular, others have not been able to reproduce the frequent Apaf-1 downregulation in melanoma cell lines (282-284) or clinical samples (284).

Histone Deacetylase Inhibitors

Although TSA was a very potent HDACi, solubility problems and lack of specificity motivated the search for other inhibitors 266 . Moreover, TSA displayed no anti-tumour activity during in vivo studies of human melanoma xenografts in nude mice, most likely due to metabolic inactivation in the liver and kidney 212 . Many HDACi have, however, used the structural characteristics of TSA as a template, including closely related compounds Malignant melanoma

Uva Uvb and Sunscreens

Some people distinguish between two forms of ultraviolet radiation and argue, fallaciously, that one is less harmful than the other. UVA has wavelengths ranging from 320 to 400 nm and UVB has wavelengths from 290 to 320 nm. (Visible light starts at about 400 nm, the deepest violet we can see.) UVA and UVB are sometimes called tanning rays and burning rays, respectively. Tanning salons often advertise that the UVA rays they use are safe, but public health authorities know better. UVA can burn as well as tan, and it inhibits the immune system, while both UVA and UVB are now thought to initiate skin cancer. As dermatologists say, there is no such thing as a healthy suntan. Whether or not sunscreens help to protect against skin cancer remains unproven. As the sale of sunscreen has risen in recent decades, so has the incidence of skin cancer. Indeed, recent studies have shown that people who use sunscreens have a higher incidence of basal cell carcinoma than people who do not, while data...

Paraneoplastic Syndromes of the CNS

Paraneoplastic OM in adults has been described in association with SCLC, non-small cell lung cancer and carcinomas of the lung, breast, kidney, and gastric ventricle as well as malignant melanoma 62,76 . Some patients harbor Ri antibodies, which may coexist with other onconeural antibodies 15 . Cancer-associated retinopathy is characterized by acute or subacute, progressive visual disturbances that affect both cone and rod function, and usually with symptoms from both eyes. The symptoms usually precede the cancer diagnosis. SCLC is by far the most common associated tumor, but cancer-associated retinopathy has also been reported in patients with non-small cell lung cancer 81 , and various types of adenocarcinoma 82 . The most commonly found antibody is directed against the 23-kDa photorecep-tor protein recoverin and is not specific to cancer-associated retinopathy 82, 83 . Several other antibodies have been described, and some patients are seronegative. Metastatic malignant melanoma is...

Therapeutic Potential Of Dppiv Inhibition

Nervosa and periodontal disease, but are decreased in systemic lupus, rheumatoid arthritis, pregnancy, depression, and schizophrenia (91-98). HIV-infected patients have normal serum DPP-IV activity but with a decreased number of DPP-IV-positive lymphocytes (99). DPP-IV has been employed as a cell surface marker in the histological evaluation of a wide range of tumor types. Tumors have been described with either increased or decreased expression of CD26 DPP-IV, and this divergent expression has been associated with both an increased and decreased aggressiveness of growth of the tumors in question. Tumors with high cell-surface DPP-IV activity expression include B chronic lymphocytic leukemia, basal cell carcinoma, T cell lymphoma, thyroid carcinoma, breast cancer, hepatocellular carcinoma, and lung tumors, while tumors with reduced or absent DPP-IV activity CD26 expression include squamous cell carcinoma and melanoma (88,100108). Presently, it is unclear whether changes in DPP-IV...

Ispinesib and related compounds

Sensitive non-small cell lung cancer, ovarian cancer, hepatocellular cancer, colorectal cancer, head and neck cancer, hormone-refractory prostate cancer, and melanoma. In the ongoing breast cancer study, women with locally advanced or metastatic breast cancer, receive ispinesib as monotherapy at 18mg m2 as a 1-h intravenous infusion for every 21 days. In an interim analysis of Stage 1 data from this two-stage trial, partial responses were reported in three of 33 evaluable patients. Maximum decreases in tumor size ranged from 46 to 68 , and the duration of response from 7.1 to 13.4 weeks. The overall response rate for all 33 evaluable patients was 9 with a median time to progression of 5.7 weeks. The adverse events were manageable, predictable, and consistent with the Phase I clinical trial experience with ispinesib, and ispinesib plasma concentrations were comparable to those observed in the Phase I clinical trial 11,16 .

Mitogenic factors in Eisenia foetida coelomic fluid as regulatory molecules

Another earthworm mitogen was detected in a glycolipoprotein complex G-90 isolated from the whole E. foetida tissue extract 17, 18 . Mitogenic effect of G-90 on mouse melanoma and fibrosarcoma cells in serum-free conditions seems to be associated with insulin-like proteins. These proteins crossreact with anti-insulin antibodies and display molecular mass of 38, 39 and 56 kDa. The presence of insulin-like growth factors was proven in various invertebrates and thus the existence of similar growth factor in earthworms is highly expected.

Glial Cells and Brain Tumors

Unmyalinated Axons Brain

A tumor consists of a mass of rapidly dividing cells. Mature neurons, however, have little capacity for mitosis and seldom form tumors. Some brain tumors arise from the meninges (protective membranes of the CNS) or arise by metastasis from tumors elsewhere, such as malignant melanoma and colon cancer. Most adult brain tumors, however, are composed of glial cells, which are mitotically active throughout life. Such tumors are called gliomas21 Gliomas usually grow rapidly and are highly malignant. Because of the blood-brain barrier (see chapter 14), brain tumors usually do not yield to chemotherapy and must be treated with radiation or surgery.

Combination therapy with DNAdamaging agents

Combination therapy of PF-1367338 and TMZ in metastatic malignant melanoma patients has been reported 47 . In this melanoma clinical trial, there was an increase in both the partial response rate and disease stabilization compared to the use of TMZ monotherapy alone. This improved response was accompanied by an increased frequency of myelosuppression. A Phase 0 clinical trial was conducted using ABT-888 50 to determine a dose range and time course that would inhibit PARP activity. The compound was rapidly absorbed, with the target Cmax exceeded at a 10 mg dose. Statistically significant PARP inhibition was observed in PBMC and tumor biopsies following single 25 and 50 mg doses. Currently, ABT-888 is being used in combination with several chemother-apeutics, and results of a Phase I study of ABT-888 combined with TMZ in patients with nonhematological malignancies and metastatic melanoma have been reported 51 . Of 20 patients evaluated, one had a partial response, and 10 had stable...

Intratumoral Microvascular Density

Some investigators have suggested that assessing intratumoral MVD or other markers of endothelial cell proliferation, such as endoglin (34), with serial tumor biopsies over time may offer an insight into the biological activity of a given AI. Unfortunately, the ability to obtain serial tumor biopsies in cancer patients has been difficult. Few tumor types manifest metastatic disease in easily accessible sites. Exceptions include malignant melanoma and Kaposi's sarcoma (KS), which often present with multiple skin lesions. Although there is much enthusiasm for evaluating AIs in patients with HIV-related KS, this disease entity may not behave in the same way as other, more typical, epithelial tumor types. The requirement for serial biopsies has been incorporated into other clinical trials, including those that attempt to determine the development of multidrug resistance (MDR) gene expression over time, as patients are treated with a particular cytotoxic chemo

Novel Method To Identify Tumorreactive T Cells Cd107 Mobilization

A key advantage of the CD 107 technique is the ability to detect tumor-reactive CD8+ T cells without knowing the peptide-MHC target. Since the assay measures T cells which degranulate in response to tumor cells, there is no a priori need to know the actual peptide target which would be required for most current assays. This is an important advantage since only a small number of TAAs have been identified to-date, mostly in the setting of melanoma. This technique may also be useful for immune monitoring of clinical trials involving vaccination with whole tumor cells, tumor-APC fusions, APCs pulsed with tumor lysates or transfected with tumor RNA, or other novel immunotherapeutic strategies in which the exact peptide targets are undefined. In such instances, the same cells used for vaccination could be used as stimulators in the immune monitoring assay to reveal tumor-reactive, cytolytic T cells.

TSP1 Is a Potent Inhibitor In Vivo

TSP-1 is effective at inhibiting angiogenesis induced by living tumor cells in several settings. Small pieces of mouse melanoma, or human colon carcinoma cut from tumors growing in nude mice and implanted directly into rat corneas, induce vessel ingrowth that is blocked when a pellet containing TSP-1 is interposed between the tumor fragment and the vascular limbus (P. J. Polverini and N. Bouck, unpublished data). Systemic treatment of mice with purified TSP-1 can also be anti angiogenic and inhibit tumor growth. High levels of TSP-1 in the circulation render mice unable to mount a corneal angiogenic response to a pellet containing stimulatory bFGF and halt the growth of experimental lung metastases (19).

Antigenic changes on malignant cells

Abnormalities in TA expression as well as a variable degree of inter- and intra-lesional heterogeneity characterize many tumors. As a result, peptides may not be generated from TA or may be formed in very low amount and the corresponding HLA class I antigen-TA peptide complexes are not formed in spite of the expression of the relevant HLA class I allospecificity. The phenomenon of TA loss has been mainly described in melanoma. Melanocytic differentiation proteins (MDPs, e.g. gp100, MART-1, TRP-1, and tyrosinase) have been found to be lost in metastatic lesions in patients with melanoma independently of the treatment with immunotherapy (120122). More recently, loss of the newly identified melanoma associated antigen, melanoma inhibitor of apoptosis protein (ML-IAP) was reported in a recurred intestinal metastasis in conjunction with a lack of lymphocyte infiltration, following immunotherapy utilizing GM-CSF-secreting autologous tumor cells as immunogens (123). In SCID mice, expansion...

Adjunctive Cryotherapy

Nevertheless, advantage from the use of adjunctive chemotherapy is likely. Cooper et al., in animal experiments, concluded that the administration of cyclophosphamide potentiated cell-mediated immunity.113 Clarke et al.,23 24 freezing prostate cancer cells in vitro, demonstrated that a combination of freezing and 5-fluouracil was associated with a greater reduction in cell survival than either freezing or the drug alone. Mir and Rubinsky,109 freezing melanoma cells in vitro, and exposing them to bleomycin, reported that the cold injury made the cells permeable to the drug, which is of therapeutic interest because bleomycin does not normally enter the cells.

Role Of Organ Environment In Pathogenesis Of Metastasis

Clinical observations of cancer patients, and studies with experimental rodent tumors, have revealed that certain tumors produce metastasis to specific organs, independent of vascular anatomy, rate of blood flow, and number of tumor cells delivered to each organ. The distribution and fate of hematogenously disseminated, radiolabeled melanoma cells in experimental rodent systems amply demonstrate that tumor cells reach the microvas-culature of many organs (33-36). Extravasation into the organ parenchyma and proliferation of tumor cells occur in only some organs therefore, the mere presence of viable tumor cells in a particular organ does not always predict that the cells will proliferate to produce metastases (33,34,37). Experimental data supporting the seed and soil hypothesis were derived from studies on the preferential invasion and growth of B16 melanoma metastases in specific organs of syngeneic mice (39). The B16 melanoma cells injected intravenously produced lesions in the lungs...

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...

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.

Peroxisome Proliferatoractivated Receptor Target Genes

Most of the PPARg target genes in adipose tissue are directly implicated in lipogenic pathways, including lipoprotein lipase, adipocyte fatty acid-binding protein, acyl-CoA synthase, and fatty acid transport protein (94). Further, PPARg ligands have been shown to inhibit the growth and induce apoptosis in cells from different cancer lineages, including liposarcoma, breast cancer, melanoma, and colon cancer, demonstrating antitumor effects (96-99).

Modulation of TSP1 Production During Tumor Development

Some tumor-suppressor genes support the production of TSP-1. When they are inactivated, the secretion of inhibitory TSP-1 falls off, and, as a result, the cells become more angiogenic. Wild-type p53 supports TSP-1 production in some breast cells (96) and in fibroblasts (27,95), although not in glioma cells (102), where TSP-1 production depends, instead, on an unidentified tumor-suppressor gene on chromosome 10p (26), possibly PTEN MCMAC (103,104). In each ofthe above cases, the phenotype of the cells switches from antiangiogenic to angiogenic upon loss of the tumor-suppressor gene, because of a decrease in the secretion of inhibitory TSP-1. In addition, expression of NM-23 can increase TSP-1 production in melanoma cells (97), suggesting that this metastasis suppressor could in some settings regulate angiogenesis via TSP.

General Considerations and Future Directions

The prognostic relevance of circulating tumor cells in the blood of patients with melanoma and colorectal cancer has been demonstrated. However, since reports showing their independent prognostic value are limited, clinical significance has yet to be fully established. Interlaboratory differences in the technique used are partly responsible for this uncertainty. Therefore, prospective trials with a standardized detection protocol, including sample pre-treatment, tumor cell enrichment, cDNA synthesis, and real-time RT-PCR amplification as well as a large cohort of patients, are needed to clarify the prognostic significance of tumor cells in the blood. B4. Brossart, P., Keilholz, U., Willhauck, M., Scheibenbogen, C., Mohler, T., and Hunstein, W., Hematogenous spread of malignant melanoma cells in different stages of disease. J. Invest. Dermatol. 101, 887-889 (1993). D1. de Vries, T. J., Fourkour, A., Punt, C. J., van de Locht, L. T., Wobbes, T., van den Bosch, S., et al.,...

Effect Of pH On Angiogenesis

It is known that the mitogenic response of a variety of cells to growth-stimulating agents are accompanied by an transient increase in Na+ H+ exchange, with a resultant increase in pHj, which suggests that alkalization of the intracellular environment may be an initial signal for cell proliferation, as well as possible cell differentiation. In this connection, Grass et al. (82) reported that cellular differentiation was stimulated by agents that increase pH and was inhibited by agents that block the ATP-dependent H+ pump (Na+ H+ ATPase). The pH in mammalian cells has been demonstrated to vary, depending on the stages of the cell cycle. In tumor cells, the pH of S-phase and G2 M cells was slightly higher than that of G0 G1 cells (83). Taylor and Hodson (84) observed that the growth rate of PMC-22 human melanoma cells in culture was normal at pHe 7.2-6.8 the growth rate was reduced as the medium pH was lowered to below 6.8. When the medium pH was lowered to 6.7-6.4, the cells...

Distribution in Tumors

Melanoma In 20 patients, oxygen tension was measured the day before the surgical removal of a suspected metastatic lesion from a primarily treated melanoma (52). An histological confirmation of the malignant origin of the removed lesion was obtained in 18 cases. In 2 cases, the removed nodes were histologically noninvaded by the known melanoma. The median pO2 for normal tissues was 40.5 mmHg. For tumors, median pO2 was 11.6 mmHg, 17.1 mmHg in nodes, and 6.7 mmHg in skin metastases. Very low values (< 2 mmHg) represented 20 of the recorded values in nodes and 15 in skin metastases. Median pO2 was 10.4 mmHg in nodes larger than 3 cm (6 patients), and 53.3 mmHg in nodes smaller than 3 cm (6 patients). For nonmetastatic nodes, median pO2 was 20.9 and 25.1 mmHg, without any value below 10 mmHg. A decrease in pO2 values, probably corresponding

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).

Angiogenesis Biomarkers for Assessing Human Disease

Circulating VEGF levels may have particular utility in determining response to treatment. Normalization of circulating VEGF levels may be associated with objective tumor response or stable disease and subsequently higher survival following treatment for malignant disease 137 . Correspondingly, increasing VEGF levels have been associated with tumor relapse, for example, in malignant melanoma 138 . High circulating VEGF levels may predict poor prognosis in early arthritis 139 . Furthermore, serum VEGF levels decrease in patients with rheumatoid arthritis who have been successfully treated 140, 141 .

Malignant Neoplasm

Common primary malignancies of the esophagus are squamous cell carcinoma and adenocarcinoma, which account for more than 90 of all such lesions. Reports of rare primaries include malignant melanoma presenting as acute hemorrhage (78), and esophageal stromal tumor typically presenting with dysphagia but rarely with acute bleeding (79). Reported cases of bleeding from metastases include breast carcinoma (80), renal cell carcinoma (81), small cell carcinoma, osteogenic sarcoma, and germ cell tumors (82) (Table 1). Esophageal carcinoma presenting as spontaneous acute upper GI bleeding is rare, with the dominant presenting symptom being dysphagia and weight loss. Large series have reported only rare cases of acute bleeding as the initial symptom (19,20,34). There is a reported case of a distal esophageal carcinoma that penetrated the aorta, leading to fistula, massive hematemesis, and death (83). In another case, a primary esophageal malignant melanoma presented with massive hematemesis...

Disease Atlases

Another set (for the rarer diseases) used the 47 counties. These atlases again showed marked variations in the distribution of disease. For example, cancer rates for the breast, ovary, brain, melanoma of the skin, and non-Hodgkin's lymphoma were lower in the north rates for cancers of the buccal cavity, pharynx, stomach, rectum, cervix and kidney were generally lower in the south. A few pockets of high mortality were evident also for example, oesophageal cancer in Lancashire, and nasal and bladder cancers in some of the London boroughs. Most importantly, these atlases stimulated the formation of new hypotheses of causation, which were tested both by the authors of the atlases and by other independent researchers.


Unraveling the Complex Relationship Between Cancer Immunity and Autoimmunity Lessons from Melanoma and Vitiligo Hiroshi Uchi, Rodica Stan, Mary Jo Turk, Manuel E. Engelhorn, Gabrielle A. Rizzuto, Stacie M. Goldberg, Jedd D. Wolchok, and Alan N. Houghton Immunity to Melanoma Antigens From Self-Tolerance to Immunotherapy

Lymphatic mapping

Sentinal lymph node identification is a technique that involves a peri-tumoral injection of a short-lived radioactive substance and or a blue dye that is then transported by the lymphatic channels to the sentinel lymph node. This modality has been routinely used in melanoma, breast cancer, penile cancer and vulvar cancer. Larger trials need to be performed in order to assess the sensitivity, specificity and safety of sentinel node detection in cervical cancer.16

Kainate Receptors

Chronic administration of IFN-a for the treatment of hepatitis C, hairy-cell leukemia, AIDS-related Kaposi's sarcoma, chronic myelogenous leukemia, and melanoma have been shown to produce depressive symptoms that adversely affect disease outcome because of their negative impact on a patient's quality of life, their interference with treatment adherence and the development of serious complications, including suicide (Ademmer et al. 2001 Valentine et al. 1998 Zdilar et al. 2000). The mechanism by which chronic IFN-a treatment induces depression is yet to be established, although serotonin-mediated effects have been implicated (Cai et al. 2005 Lotrich et al. 2009 Menkes and MacDonald 2000). In vitro studies have demonstrated that IFN-a treatment of glioblastoma cell lines can alter the editing pattern for 5HT2C transcripts by increasing the expression of the IFN-inducible isoform of ADAR1 (p150) (Yang et al. 2004), providing a mechanism by which cytokines could induce depression by...

High Tech Equipment

With a laser one can cut, coagulate, and remove small tumours, Tattoos and port-wine stains react well to laser therapy. Care should be taken with pigmented moles, however a very experienced diagnostician must first dispel any final suspicion of a malignant pigmented tumour - malignant melanoma.


Primary prevention trials of beta-carotene in well-nourished populations have demonstrated no reduction in CVD or cancer (ATBC, Skin Cancer Prevention Study, CARET, PHS, WHS), and some studies have raised the possibility of harm (ATBC, CARET). The few secondary prevention trials have also failed to show any benefit of beta-carotene supplementation. A meta-analysis of major beta-carotene trials found a slight increase in both total and CVD mortality. At this time beta-carotene supplementation cannot be routinely recommended for either the primary or secondary prevention of CVD.

Vaginal Cancer

Patients with melanomas and sarcomas represent a rare group of patients that require special consideration for treatment. Primary surgery with or without adjuvant radiotherapy is more frequently used for patients with advanced stages of melanoma. Alternatively, primary radiation may be used and is typically administered in the form of an external beam. The survival rate for patients with melanomas is poor regardless of the treatment implemented.

Tumor Antigens

It is tempting to speculate that other tumor antigens can also be processed by macroautophagy. Indeed, there are an increasing number of MHC class II epitopes derived from melanoma antigens that are described as being processed via an endogenous route onto MHC class II molecules (Godefroy et al. 2006 Zarour et al. 2000). Cytosolic melanoma antigens such as Melan-A MART-1 or MAGE3 that lack a sorting signal to melanosomes and are not expressed on the cell surface could represent a potential pool of macroautophagy substrates. Clearly more studies are needed to assess which tumor antigens can gain access to MHC class II presentation and CD4+ T cell stimulation. A better understanding of tumor immune surveillance by CD4+ T cells after macroautophagy could provide insights into how adaptive tumor immune responses are influenced by macroautophagy regulation in tumors.

Future Directions

Another approach involves generation of activating point mutations within the promoter region as has been in the case of AFP promoter 126 and the MDR 1 promoter 127 . Yet another strategy involves selective combination of multiple positive regulatory and tissue-specific elements to achieve enhancement of weak promoters. This strategy has shown promising results in augmenting melanoma-specific gene expression when the tyrosinase promoter, either alone or in combination with single or dual, tandem melanocyte-specific enhancer, was used to drive the expression of luciferase and the E. coli purine nucleoside phosphorylase gene.

Oral administration

Removal of hypoxanthine in Lesch-Nyhan Disease, removal of tyrosine in melanoma and removal of uremic waste metabolites in kidney failure. For oral administration, very strong polymeric membranes that will not break down in the presence of powerful digestive enzymes in the intestine are needed and are being developed (Chen et al., 2006). Furthermore, a buffer should be added to the oral formulation to protect the enclosed cells during their passage through the acidic environment of the stomach. There are other requirements needed for the most optimal use of oral administration and this is being studied (Chen et al., 2006) As with all medical therapies, different conditions will require different types of approaches for the use of artificial cell encapsulated cells either implantation, insertion or oral administration, as appropriate.

Natural lignans

The naturally occurring lignan picropodophyllotoxin (PPP) or AXL-1717, 34, has recently advanced into human clinical trials (oral dosing) 79,80 . The epimeric podophyllotoxin 35 (PPT), a cytotoxic agent known for its potent antimitotic activity, is also reported to be an IGF-1R selective substrate inhibitor. Both 34 and 35 are reported to inhibit IGF-1R catalyzed substrate phosphorylation of pGT with an IC50 value of 6 nM. Antiproliferative IC50 values against 11 cell lines for both compounds are between 20 nM and 25 nM. In preclinical models, 34 is efficacious when dosed intraperitoneally in a wide range of tumor models such as breast, prostate, malignant melanoma, and multiple myeloma. Results from cell culture studies using IGF-1R-deficient cell lines, mouse embryonic fibroblasts (MEFs), and HepG2 cells have called into question whether the observed antitumor activity is due to IGF-1R inhibition 81,82 .


Both T- and NK-cells have been implicated as antitumor effector cells (91), and IFN-y has been shown to have antitumor activity in animals (92,93). IL-12 has the potential to be used as an immunomodulatory cytokine in the therapy of malignancies (92,94,95), as well as in gene therapy (96,97). Brunda et al. (87) have shown that systemic administration of murine IL-12 can slow, and, in some cases, inhibit, the growth of both established sc tumors in mice and experimental pulmonary or hepatic metastases of B16F10 murine melanoma, M5076 reticulum cell sarcoma, or RenCa renal cell adenocarcinoma, and that local peritumoral injections of IL-12 can result in regression of established sc tumors. Based on results obtained using mice deficient in lymphocyte subsets, and an antibody depletion experiments, Brunda et al. (87,98) concluded that the antitumor efficacy of IL-12 is mediated primarily through CD8+ T-cells.

Molecular Imaging

Tion of neuroendocrine tumour cells and pancreatic endocrine cells and exemplifies the in vivo visualisation of cell types in their natural surrounding, based on their molecular properties. Following injection of the labelled molecule, even such detailed analysis as observation of cell surface binding, internalisation of the dye and renal excretion was possible by confocal microscopy in a living organism, illustrating the visualisation of molecular events in vivo 1 . Anikajenko et al used an FITC antibody to human avb3 integrin complex (vitronectin receptor,expressed in high levels on melanoma cells) to enable in vivo microscopy of human melonoma cells xenografed into nude mice. These studies demonstrate that in vivo molecular imaging by confocal endomicroscopy can be achieved and is able to identify malignant cells (O Fig. 9.4a).

Cell Biology Studies

TNP-470 has been shown to be effective in decreasing the growth of primary tumors and the growth and incidence of pulmonary, hepatic, and lymph node metastases in a wide variety of rodent homograft and xenograft models, using a variety of dosing schedules and routes of administration. In most instances, antitumor effects were dose-dependent. Rodent tumor models included hemangioendothelioma, melanoma, osteosarcoma, reticulum cell sarcoma, glioma, hepatoma, fibrosarcoma, and mammary, lung, bladder, tongue, and pancreatic carcinomas. Human xenograft models included glioblastoma, neuroblas-toma, medulloblastoma, meningioma, fibrosarcoma, neurofibrosarcoma, rhabdomyosar-coma, and gastric, colon, breast, prostate, and esophageal carcinomas. No antitumor activity was reported in these cases a rat astrocytoma (11), a human endometrioid carcinoma (12), and a human gastric carcinoma (12). With few exceptions, weight loss or failure to gain weight was observed in animals receiving high doses of...

Patient Demographics

Adenocarcinomas comprised the largest class of tumors tested in the four phase I studies (45.5 ). Sarcomas represented 27.3 , with leiomyosarcomas accounting for more than half of these cases, and squamous cell carcinomas contributed 19.8 . The remaining 7.4 consisted of five cases of melanoma, and single cases of various tumor types.


The phase I experience with TNP-470, described in detail in Section 8., reflects this situation. Seven patients experienced disease stabilization of at least 5 mo duration, and one cervical cancer patient had a CR (48-50). TNP-470 was administered under the same schedule (1-h infusion qod for 28 d, followed by a 14-d rest period) to prostate and cervical cancer patients. One prostate cancer patient with bone metastases was treated for 9 mo at 9.3 mg m2 prior to disease progression. Two cervical cancer patients were treated for 5 and 6.5 mo, respectively, before their disease progressed. These patients were permitted intrapatient dose escalations (14 47.5 and 31.5 47.5 71 mg m2, respectively). A third cervical cancer patient has been treated for more than 18 mo, and continues on treatment at 60 mg m2, with serial assessments of stable disease. When TNP-470 was administered as a 4-h infusion once weekly, three patients experienced disease stabilization. A patient with metastatic...


Eisen and colleagues studied 48 patients with advanced solid tumors, with a thalidomide dose of 100 mg qHS (24). This cohort included 17 individuals with ovarian cancer, 16 with melanoma, 8 with renal cell carcinoma, and 7 with breast cancer. Three patients responded to therapy, and an additional 10 patients had disease stabilization for up to 25 wk. Of particular interest was that patients with progressive disease developed rising serum and urinary VEGF levels, whereas patients with stable disease showed stable or falling VEGF levels. In addition, four patients had measurable serum bFGF, and all had rapidly progressive disease.