Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of beta-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after beta-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. beta-Lapachone causes cell-cycle delays in late G(1) and S phase, and taxol arrests cells at G(2)/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.
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PMID:Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints. 1055 27

As part of a search for causative genes of familial pancreatic carcinoma, the p16 genes were sequenced in members of 21 families with a phenotype of familial pancreatic carcinoma (2 or more first degree relatives affected). One family was found in which members carried a novel p16 allele with a G to T transversion at position 451, creating a missense amino acid change at codon 145 (Asp to Cys) and possibly disrupting the donor splice site of the exon 2/3 boundary. This coding change is not a known polymorphism, and occurs at a codon position in which another missese/splicing change has been shown to be linked to familial melanoma/pancreas cancer.
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PMID:Novel germline p16(INK4) allele (Asp145Cys) in a family with multiple pancreatic carcinomas. Mutations in brief no. 148. Online. 1062 32

Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to date. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality.
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PMID:The genetics of hereditary melanoma and nevi. 1998 update. 1063 Jan 72

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized that unselected patients with both primary cancers, i.e., pancreatic cancer and malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourteen patients, with both pathologically verified pancreatic adenocarcinoma and melanoma, were assessed for germline CDKN2A mutations by polymerase chain reaction amplification and sequencing of six overlapping fragments encompassing exons 1alpha and 2. A yeast two-hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: I49S, a novel substitution in exon 1alpha, and M53I, a previously reported missense mutation in exon 2. Both variants lead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations. This finding has important implications not only for the proband, but also for other family members.
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PMID:Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. 1071 65

Familial atypical multiple mole melanoma (FAMMM) is an autosomal dominant disease characterized by the familial occurrence of malignant melanoma of the skin and multiple atypical precursor lesions. Germline mutations in the p16 (CDKN2A) gene have been reported in at least a quarter of such families. An association has been reported between p16 mutations and pancreatic cancer. The aim of this study was to assess the risk of developing pancreatic and other cancers in Dutch FAMMM families with a 19 bp deletion in exon 2 of the p16 gene (p16-Leiden). Mutation analysis was performed in 27 families suspected of FAMMM. Clinical and pathological data were collected from all relatives affected with cancer. A p16-Leiden mutation was identified in 19 families. These families included 86 patients with melanoma. The second most frequent cancer was pancreatic cancer, which was observed in 15 patients from 7 families. The mean age at diagnosis of pancreatic cancer was 58 years (range 38-77 years). The estimated cumulative risk of developing pancreatic cancer in putative mutation carriers by age 75 years was 17%. In 8 p16-Leiden-negative families, no cases of pancreatic cancer occurred. p16 mutation carriers have a considerable risk of developing pancreatic cancer. Further studies should evaluate the value of surveillance of the pancreas in these high-risk families.
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PMID:Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). 1095 90

Pancreatic cancer is one of the most aggressive malignant tumors, with an overall survival rate of 2%. The identification of growth factors that contribute to the malignant phenotype can help to identify new targets for therapy. In this study, we analyzed the growth factor pleiotrophin (PTN) that was originally described as a developmentally regulated cytokine during early embryogenesis. More recently, PTN was found to be overexpressed in a variety of neuroectodermal tumors and described as an essential angiogenic growth factor in choriocarcinoma and melanoma, promoting metastatic growth. Recently, we discovered high expression levels of PTN in patients with gastrointestinal malignancies, particularly in those patients with pancreatic cancer. However, it is not known whether PTN is a contributor to the growth of pancreatic cancer or is only a bystander. We used ribozymes to deplete PTN mRNA from Colo357 pancreatic cancer cells and studied the resulting phenotype. The reduction of PTN resulted in a decrease in the proliferation rate, soft agar colony formation, and tumor growth in animals. Supplementation of cells with PTN partially reversed the ribozyme effect. The autocrine function of PTN was confirmed by using PTN-binding antibodies that inhibited the proliferation rate by 50% in Colo357 cells but also in a different pancreatic cancer cell line, Panc89. Our study identifies PTN as a new and essential growth factor for pancreatic cancer. Due to the restricted expression pattern of PTN in adults, PTN is suggested as a target for pancreatic cancer therapy.
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PMID:Pleiotrophin can be rate-limiting for pancreatic cancer cell growth. 1101 59

The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.
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PMID:Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families. 1111 97

Virulizin(R) (registered trademark of Lorus Therapeutics, Inc.) is a novel biological response modifier (BRM) that enhances cell-mediated immune response to tumour cells by direct macrophage activation. The agent, an aqueous solution containing a 5% (w/v) solid material mixture comprised of inorganic salts (95 - 99% of the dry weight) and organic compounds of molecular weight < 3000 Daltons (1 - 5% of the dry weight), is provided as a sterile, injectable formulation. Virtually all the organic compounds and ionic components in the mixture have been identified by chemical and spectroscopic methods. Virulizin(R) is obtained from bovine bile by a standardised process involving solvent extraction and heat hydrolysis. In vitro studies have shown that Virulizin(R) can stimulate blood monocytes, peritoneal macrophages and alveolar macrophages from patients with malignant and non-malignant diseases to mediate a level of tumour cell cytolysis that is equal to, or greater than, that elicited in the same cells by other, more conventional biological activators. Other studies have shown that the stimulation of cytotoxic function by Virulizin(R) is insensitive to the inhibitory effects of prostaglandins and, hence, is distinct from many other activators. Furthermore, the blood monocytes of patients currently receiving cytotoxic chemotherapy showed activation with Virulizin(R). In preclinical studies, Virulizin(R) showed modest inhibition of tumour growth in a human pancreatic cancer xenograft model (T/C, 0.60; p = 0.012) and increased survival time by 8% (p = 0.046) in a murine melanoma model. Toxicity studies in rats indicated that Virulizin(R) injected intramuscularly was well-tolerated by the animals. Except for a lower rate of body weight gain in the high dose group, no toxicological effect related to treatment was observed in a chronic 13-week study (three weekly im. injections of up to 1.1 ml/kg). Mutagenicity studies with Virulizin(R) were negative. Many Phase I/II and Phase II clinical trials were carried out with Virulizin(R) to evaluate the safety and efficacy of the agent to treat cancer patients. Three of those studies involved the treatment of patients with pancreatic adenocarcinoma. The majority of patients participating in these studies were those who had failed conventional treatment including surgery or chemotherapy. Disease stabilisation was observed in patients treated with Virulizin(R), and, based on a meta-analysis of the data from the three studies, the survival of the patients treated with Virulizin(R) was better than a similar patient population receiving standard chemotherapeutic agent for that disease indication. However, randomised studies may be required to confirm the effect of Virulizin(R) on disease stabilisation and survival. In the three studies on patients with malignant melanoma, at least 69% treated with Virulizin(R) showed no additional deterioration or had improved at four weeks with response being only slightly reduced after eight weeks. In the evaluation of safety, assessed overall from these clinical studies in 200 patients treated with Virulizin(R), the number and severity of adverse events were small. In conclusion, Virulizin(R) is a novel, clinically non-toxic biological response modifier that appears to have a clinical effect on disease stabilisation and survival in patients with pancreatic cancer and malignant melanoma. However, additional randomised studies may be required to confirm those effects. Future studies on Virulizin(R) will focus on the characterisation of the active components in the agent and the development of a synthetic formulation. Subsequently, the preclinical and clinical pharmacokinetics of Virulizin(R) will be determined and studies to optimise the human dose of the agent will be carried out.
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PMID:Virulizin(R) - A review of its antineoplastic activity. 1113 22

Purpose: At the University Of Pittsburgh Medical Center, over 100 oncology studies have been performed using a combined PET/CT scanner. The scanner is a prototype, which combines clinical PET and clinical CT imaging in a single unit. The sensitivity achieved using three-dimensional PET imaging as well as the use of the CT for attenuation correction and image fusion make the device ideal for clinical oncology. Clinical indications imaged on the PET/CT scanner include, but are not limited to, tumor staging, solitary pulmonary nodule evaluation, and evaluation of tumor reoccurrence in melanoma, lymphoma, colorectal cancer, lung cancer, pancreatic cancer, head and neck cancer, and renal cancer.Methods: For all studies, seven millicuries of F(18)-fluorodeoxyglucose is injected and a forty-five minute uptake period is allowed prior to positioning the patient in the scanner. A helical CT scan is acquired over the region, or regions of interest followed by a multi-bed whole body PET scan for the same axial extent. The CT scan is used to correct the PET data for attenuation. The entire imaging session lasts 1-1.5 hours depending on the number of beds acquired, and is generally well tolerated by the patient.Results and Conclusion: Based on our experience in over 100 studies, combined PET/CT imaging offers significant advantages, including more accurate localization of focal uptake, distinction of pathology from normal physiological uptake, and improvements in evaluating therapy. These benefits will be illustrated with a number of representative, fully documented studies.
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PMID:7. Survey of Results of Whole Body Imaging Using the PET/CT at the University of Pittsburgh Medical Center PET Facility. 1115 Jul 64

The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs [alpha--(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP], which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
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PMID:Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. 1117 70


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