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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species (ROS) have been frequently implicated in the initiation and promotion phases of carcinogenesis. Antioxidant enzymes, which can antagonize this process, are lowered in a number of malignancies. The enzyme most commonly decreased is the mitochondrial Mn-containing superoxide dismutase (MnSOD) encoded by a nuclear gene mapped on the band 6q21, a region frequently deleted in several human tumours. The close association of del(6q) with diminution of MnSOD has led to suggest that MnSOD might be a new type of tumour-suppressor gene. This hypothesis is also sustained by the finding that transfection of MnSOD cDNA into human melanoma cell lines suppress the malignant phenotype. There are, however, conflicting observations that tend to ascribe the deficiency of the MnSOD activity more to a defect in the expression of the gene than to its deletion. In many transformed cell lines, including some with marked del(6q), there is no change in the dosage of the MnSOD gene and the enzyme is highly inducible by various pro-oxidant agents. Transition metals (Mn, Fe) have been found to be highly deficient in human and rodent tumours. Owing to the second messenger function of ROS in activating transcription factors (NF-kB, AP-1) and to the ability of Mn to facilitate the dismutation of O2- to H2O2 and of Fe to participate in the Fenton reaction, we propose that in the early stage of carcinogenesis an impairment of the signal transduction machinery, related to the metal deficiency, might limit the binding to DNA of transcription factors and cause the defect in the MnSOD gene expression.
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PMID:Defective gene expression of MnSOD in cancer cells. 826 40

Glutathione transferases (GSTs) are enzymes involved in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We investigated the melphalan sensitivity together with activity and cellular concentration of GST isoenzymes of human melanoma cell line RPMI 8322 in different phases of the cell cycle. By centrifugal elutriation three cell fractions containing different proportions of cells in the G1 phase were isolated. Melphalan sensitivity was estimated by the colony formation assay. The cell fraction with the largest proportion of G1 cells was more sensitive to the drug than the fractions enriched in S and G2 cells. The GST activity of the cell fractions was measured with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate and the concentrations of GST P1-1, GST M1-1 and GST A1-1 were quantitated by use of isoenzyme-specific ELISA. The results show that there were less GST activity and lower GST P1-1 and A1-1 concentrations in the G1 cell enriched fraction, demonstrating a cell cycle dependence of GST expression. Thus, the cell fraction most sensitive to melphalan had the highest proportion of G1 cells and displayed the lowest GST activity, suggesting that the cell cycle dependent sensitivity to melphalan may at least partially depend on the expression of GSTs.
Carcinogenesis 1994 Jan
PMID:Cell cycle dependent sensitivity of human melanoma cells to melphalan is correlated with the activity and cellular concentration of glutathione transferases. 829 55

Twelve x-ray-induced transcripts (xips), differentially expressed 8- to 230-fold in x-irradiated versus unirradiated radioresistant human melanoma (U1-Mel) cells, were isolated as cDNA clones (xip1 through xip12) after four rounds of differential hybridization. Northern analyses revealed rare, medium, and abundant xips, ranging in size from 1.2 to 10 kb. All transcripts were transiently expressed and induced by low, but not by high (> 600 cGy), doses of radiation. Three transcripts (xip4, -7, and -12) were induced only by ionizing radiation, and many (i.e., xip1, -2, -3, -5, -6, -8, -9, -10, and -11) were also induced by UV irradiation or phorbol 12-myristate 13-acetate. Heat shock did not induce any of the xips, but it decreased basal levels of xip4, -7, -11, and -12. Three xip cDNA clones were identified as encoding thymidine kinase, DT diaphorase, and tissue-type plasminogen activator. The remaining nine cDNA clones showed little homology to known genes. Three clones contained regions homologous to c-fes/fps protooncogene, recombination activating gene 1, or the human angiogenesis factor gene. X-ray-inducible genes may function in damaged cells to regulate DNA repair, apoptosis, mutagenesis, and carcinogenesis.
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PMID:Isolation of x-ray-inducible transcripts from radioresistant human melanoma cells. 834 36

Introduction of a normal human chromosome 6 into human melanoma cell lines results in suppression of tumorigenicity. This suggests that a gene(s) on chromosome 6 controls the malignant phenotype of human melanoma. Because antioxidants can suppress the tumor-promotion phase of carcinogenesis, and because the antioxidant enzyme manganese superoxide dismutase (MnSOD) has been localized to a region of chromosome 6 frequently lost in melanomas, we have examined the effect of transfecting sense and antisense human MnSOD cDNAs into melanoma cell lines. Cell lines expressing abundant (+)-sense MnSOD-5 cDNAs significantly altered their phenotype in culture and lost their ability to form colonies in soft agar and tumors in nude mice. In contrast, the introduction of antisense MnSOD or +psv2neo had no effect on melanoma tumorigenicity. These findings indicate that stable transfection of MnSOD cDNA into melanoma cell lines exerts a biological effect that mimics that observed after introduction of an entire human chromosome 6.
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PMID:Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. 846 31

Carcinogenesis is a multigenic phenomenon where 3 prevailing types of genes are involved: oncogenes which stimulate the cell proliferation, tumor suppressor genes which act as inhibitors and metastagenes which contribute to the tumor progress. In animal models it has been shown that epithelial skin carcinogenesis proceeds stepwise: initiation, promotion, premalignant progression and finally malignant conversion. The oncogene c-H-ras and the tumor suppressor gene P53 are the genes whose involvement in these steps of epithelial skin cancers are duly established. Less experimental data are available concerning melanoma. the role of the oncogene N-ras, the tumor suppressor gene MTS-1 (encoding for protein p16) ans the metastagene nm 23 has recently be emphasized. Some cytogenetic abnormalities on chromosomes 1, 6, 9, 10, 11 and 17 have also been observed and incite to look for other genes potentially involved in the development of this tumor.
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PMID:[Genetic bases of cutaneous tumors]. 852 16

Experimental studies have demonstrated that carcinogenesis is a multistep process in which inappropriate proliferation of cells is a critical determinant. Polyamines support sustained growth and are highly regulated in all cells. The rate limiting enzyme for this pathway is ornithine decarboxylase (ODC), an enzyme that exhibits rapid turnover, and converts the amino acid ornithine to putrescine, which in turn is converted to the longer chain amines spermidine and spermine. In animal models of colon carcinogenesis, inhibition of ODC by difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor, reduces the number and size of colon adenomas and carcinomas. DFMO was first ineffective when used clinically to treat acute leukemia or melanoma and caused clinically significant but reversible ototoxicity. Subsequently, we performed a series of analyses demonstrating that hearing loss was rare below a total cumulative dose of 150 gm/m2 and increased with total cumulative dose of DFMO. The hearing loss was reversible with rapid reversion to baseline hearing. We and others have conducted Phase IIa trials to determine the lowest dose at which DFMO can decrease colon mucosa polyamine content, and found that an oral dose as low as 0.25 gm/m2 per day (perhaps lower) decreases colon tissue putrescine content and lowers the spermidine/spermine ratio. We are currently conducting a long-term randomized Phase IIb trial which serially measures the long-term effect of several low doses (and placebo) of DFMO on sustaining polyamine depletion in colon mucosa, as well as carefully monitoring hearing by audiometry and other sophisticated tests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer. 853 89

There are three main types of skin cancers: basal cell carcinoma, squamous cell carcinoma and melanoma. They are very different in terms of clinical presentation, evolution, and prognosis. Their frequency is increasing and there is sufficient evidence for the aetiological role of solar ultraviolet radiation (UVR). This evidence is based largely on epidemiological studies, animal models and studies of xeroderma pigmentosum patients. The risk of squamous and basal cell carcinoma increases with chronic solar exposure while the risk of melanoma seems to be more influenced by intermittent exposures. The physiopathological mechanisms of UV carcinogenesis are not yet entirely understood. One of the main factors seems to be mutagenesis due to impaired DNA photoproducts repair. Alteration in immune function and genesis of free radicals induced by exposure to UVR may also play a central role in UV carcinogenesis.
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PMID:[Cancers of the skin, relations to ultraviolet rays]. 854 68

Retinoids are biologic response modifiers that are present in normal skin and may possibly be perturbed in carcinogenesis. To examine this possibility in human skin, we analyzed vitamin A and cytosolic retinoid binding proteins (cellular retinol binding protein and cellular retinoic acid binding protein [CRABP]) in a total of 38 non-melanoma skin tumors and 25 healthy skin samples using high performance liquid chromatography, radioligand electrophoresis, and reverse transcriptase-polymerase chain reaction. The mean +/- SEM retinol concentration was normal in basal cell carcinoma (0.60 +/- 0.10 microM) and seborrheic keratosis (0.47 +/- 0.07 microM), but increased in keratoacanthoma (1.60 +/- 0.41 microM) and squamous cell carcinoma (1.17 +/- 0.28 microM) (p < 0.05 for both). Also, the concentrations of 3,4-didehydroretinol, a major vitamin A metabolite produced in human skin, were markedly elevated (6-7 times normal) in keratoacanthoma and squamous cell cancer. All types of tumors showed moderately increased levels of cellular retinol binding protein. In addition, keratoacanthoma and squamous cell cancer showed markedly increased levels (6-7 times normal) of CRABPII protein. Transcriptional activity of the CRABPII gene was demonstrated in both normal and neoplastic epidermis, but clear CRABPI mRNA expression was found only in basal cell carcinoma. The data indicate that characteristic perturbations of the vitamin A and retinoid binding protein levels occur in squamous cell-derived skin tumors, but whether these reflect intrinsic errors in retinoid metabolism or are secondary to abnormal cellular differentiation is unknown.
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PMID:Increased concentrations of 3,4-didehydroretinol and retinoic acid-binding protein (CRABPII) in human squamous cell carcinoma and keratoacanthoma but not in basal cell carcinoma of the skin. 861 41

Protein kinase C (PKC) plays a pivotal role in modulating the growth of melanocytic cells in culture. We have shown previously that a major physiological substrate of PKC, the 80 kDa myristoylated alanine-rich C-Kinase substrate (MARCKS), can be phosphorylated in quiescent, non-tumorigenic melanocytes exposed transiently to a biologically active phorbol ester, but cannot be phosphorylated in phorbol ester-treated, syngeneic malignant melanoma cells. Despite its ubiquitous distribution, the function of MARCKS in cell growth and transformation remains to be demonstrated clearly. We report here that MARCKS mRNA and protein levels are down-regulated significantly in the spontaneously derived murine B16 melanoma cell line compound with syngeneic normal Mel-ab melanocytes. In contrast, the tumourigenic v-Ha-ras-transformed melanocytic line, LTR Ras 2, showed a high basal level of MARCKS phosphorylation which was not enhanced by treatment of cells with phorbol ester. Furthermore, protein levels of MARCKS in LTR Ras 2 cells were similar to those expressed in Mel-ab melanocytes. However, in four out of six murine tumour cell lines investigated, levels of MARCKS protein were barely detectable. Transfection of B16 cells with a plasmid containing the MARCKS cDNA in the sense orientation produced two neomycin-resistant clones displaying reduced proliferative capacity and decreased anchorage-independent growth compared with control cells. In contrast, transfection with the antisense MARCKS construct produced many colonies which displayed enhanced growth and transforming potential compared with control cells. Thus, MARCKS appears to act as a novel growth suppressor in the spontaneous transformation of cells of melanocyte origin and may play a more general role in the tumour progression of other carcinoma.
Carcinogenesis 1996 Apr
PMID:MARCKS functions as a novel growth suppressor in cells of melanocyte origin. 862 78

Mutations of the p53 tumor-suppressor gene are the most common genetic alterations in human cancer, found in approximately 50% of all tumors. The importance of p53 in human cancer attracts attention in molecular studies dealing with the pathogenesis, diagnosis and prognosis in tumor pathology. This review summarizes the current understanding of p53 both on the genetic and protein level. Frequency and spectrum of somatic p53 mutations in the carcinogenesis of breast cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, squamous-cell carcinoma of the skin and malignant melanoma are discussed including our own investigations and studies published in the literature.
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PMID:[Tumor suppressor gene p53. Theoretical principles and their significance for pathology]. 871 Jul 88


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