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)

Experimental efforts to identify characteristic features of metastatic subpopulations have led to the selection of strains of specialized cells with high and low metastatic potential in the hope that by studying their biochemical and biophysical properties we might start to clarify how tumour cells metastasize. We report data on the phospholipid composition of three variants of murine melanoma B16: F1, with low metastatic potential; F10, highly metastatic when injected i.v.; and BL6, highly metastatic, spontaneous metastases developing from a primary s.c. tumour. Cells were studied at different stages of growth: subconfluent cultures (40-70 x 10(3) cells/cm2) or dense cultures (140-170 x 10(3) cells/cm2). Total phospholipid content decreased as cell density increased in all variants; these changes can probably be related to the reduction in cell volume with increasing cell numbers in the well. As a consequence of this reduction, the amounts of individual phospholipids also decreased in dense cultures. Phosphatidylinositol behaved differently in the highly metastatic variants. In the F1 strain it was three times lower than would be expected from the total phospholipid reduction, while in F10 and BL6 levels increased when cell density increased. Differences in phosphatidylinositol level were also found between variants within each density, suggesting that phosphoinositide synthesis may be related to the metastatic potential of the variants. Incorporation of ([3H] myo)-inositol incorporation into phospholipids over a period of 4 h was greater in F1 cells than in F10 and BL6 at both cell densities.(ABSTRACT TRUNCATED AT 250 WORDS)
Melanoma Res 1992 Nov
PMID:Phospholipid composition, phosphoinositide metabolism and metastatic capacity in murine melanoma B16 variants at different stages of growth. 133 2

It may be possible to use the melanogenic pathway as a therapeutic targeting strategy for melanoma, and encouraging clinical pilot studies of 4-hydroxyanisole have led to the search for more active analogue substrates of tyrosinase. A recent study of a range of alkoxy- and alkylthio-phenol analogues of tyrosine has shown that sulphur-containing compounds exhibit different behaviour to that of similar oxygen-containing compounds, indicating modified reactivities of their corresponding tyrosinase-induced o-quinones towards crucial cellular targets, in particular, thiols. We have therefore examined by pulse radiolysis the reactivities of a group of unstable alkylthio- and alkoxy-substituted o-quinones towards the biologically relevant thiols, cysteine and glutathione. The o-quinones were generated by rapid (microsecond) one-electron oxidation of the corresponding stable synthesized catechols, forming semiquinones which disproportionated over milliseconds to o-quinones. The latter reacted with the thiols in a pH-dependent manner, indicative of increased nucleophilicity of the thiolate anions as compared with their protonated forms, with rate constants in the region of 10(5)-10(6) M-1s-1. At pH 7.2, within the physiological range, the alkylthio-substituted o-quinones reacted with the thiols approximately 5-10 times faster than the alkoxy-substituted o-quinones. The corresponding alkylthio-substituted phenols might, therefore, in principle, be expected to be more effective targeted anti-melanoma drugs than their alkoxy-substituted counterparts. NMR studies of the reactions of several of the quinones with cysteine indicate that, where addition occurs, the product is exclusively the 6-S-cysteinyl-4-substituted-catechol.
Melanoma Res 1992 Dec
PMID:Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents. 133 96

Resistance to alkylating agents has been correlated with cellular levels of reduced glutathione (GSH) and glutathione-S-transferase (GST). GSH is also involved in regulation of melanin synthesis. Therefore, we examined sensitivity to melphalan as a function of differentiation and GSH/GST levels in three human melanoma cell lines. The Me8 cell line, classified as undifferentiated on the basis of cell shape, absence of pigment, insignificant dopa oxidase activity and presence of inhibitors of dopa-melanin formation, showed the lowest GST activity among the cell lines investigated. GLL19 cells exhibited normal differentiation as indicated by the presence of dendrites, typical eumelanosomes, melanin granules and dopa oxidase activity. These cells showed the highest GSH content and the highest GST activity. The JUSO cell line showed incomplete differentiation, and its dopa oxidase and GST activities were intermediate between the Me8 and GLL19 cell lines. The sensitivity of melanoma cell lines to melphalan increased with their degree of differentiation; it was lowest for Me8, intermediate for JUSO and highest for GLL19. Dibutyryl cyclic AMP (dbcAMP) enhanced melphalan toxicity against Me8 cells. Depletion of intracellular GSH with buthionine sulphoximine (BSO) resulted in a three-fold increase in melphalan sensitivity in all three cell lines. Our results indicate that melphalan toxicity is related to cell differentiation and GSH status of melanoma cells. Based on the observed relationship between dopa oxidase, GSH/GST levels and drug toxicity, it is proposed that competition for the GSH pool between quinonoid melanin intermediates and melphalan could diminish drug conjugation and increase cytotoxicity.
Melanoma Res 1992 Dec
PMID:Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells. 133 97

MTS1 is a metastasis-associated gene highly expressed in highly metastatic tumours. NM23 has been described as a putative metastasis suppressor gene. Here we show that thapsigargin (which raises intracellular calcium [Ca2+]i from intracellular stores) and verapamil (which blocks Ca2+ influx) both down-regulate MTS1 and NM23 gene expression in the poorly metastatic F1 and highly metastatic ML8 variants of the B16 murine melanoma without altering their metastatic behaviour. The data presented here suggest that Ca2+ released from intracellular stores could be functionally differentiated from influxed Ca2+ and could be activating different components of the Ca2+ signalling system. Many of the cellular responses to calcium are mediated through calmodulin. We have therefore further investigated the role of Ca2+ in the regulation of the MTS1 and NM23 genes using the calmodulin inhibitor W-7. Both these genes were down-regulated after treatment of the F1 and ML8 cell variants. We have shown previously that retinoic acid reduces lung colonization by the highly metastatic variant ML8 and that melanocyte stimulating hormone (MSH) enhances lung colonization by the poorly metastatic variant F1, with corresponding changes in the relative expression of NM23 and MTS1. Here we have found that verapamil and thapsigargin have no effect on lung colonization, possibly due to both genes being down-regulated. These data support the concept that NM23 and MTS1 gene expression is linked and that metastatic potential may be determined by their relative expression.
Melanoma Res 1992 Dec
PMID:Modulators of intracellular Ca2+ and the calmodulin inhibitor W-7 alter the expression of metastasis-associated genes MTS1 and NM23 in metastatic variants of the B16 murine melanoma. 133 98

The involvement of signal transduction systems in the initial attachment of two murine B16 melanoma clones of differing metastatic potential to extracellular matrix components was examined to learn more of the early events in cell-matrix interaction. Clones of high and low metastatic capacity attached similarly in the absence of any stimulators, exhibiting a two phase time course of attachment with 100% attachment by 60 min. A slight difference in attachment characteristics between the clones was seen in response to phorbol ester stimulation, which significantly inhibited attachment of the low metastatic clone but which had no effect on the highly metastatic clone. Total protein kinase C activity and distribution was similar for both clones. Attachment of both clones was severely reduced, however, if intracellular calcium was elevated or intracellular calmodulin inhibited. This study suggests that signal transduction mechanisms are involved in melanoma cell attachment to matrix proteins and offers an approach to pharmacological manipulation of these cell-matrix interactions which may be relevant to reducing metastatic spread.
Melanoma Res 1992 Dec
PMID:Intracellular regulation of cell adhesion to extracellular matrix components in murine B16 melanoma cells. 133 99

Cell free extracts from metastases of human melanoma contain a highly active ribonucleoside diphosphate reductase (RR) which uses guanosine diphosphate (GDP) as substrate and deoxythymidine triphosphate (dTTP) as effector. No activity could be detected in these extracts when cytidine diphosphate (CDP) was used as the substrate with adenosine triphosphate (ATP) as effector. The activity of this RR required the presence of either magnesium or calcium: there was a time lag before cell extracts from melanotic melanoma metastases showed full activities, but extracts from amelanotic tumors showed normal kinetics in the presence of these divalent cations. By contrast to other RRs, the activities in cell-free extracts could not be inhibited by hydroxyurea (10(-2) M). Even though an activity related free radical could be detected by electron paramagnetic resonance spectroscopy at 77 degrees K, the signal could not be quenched by 10(-2) M of this free radical trap. However, after ammonium sulphate fractionation, enzyme activity from melanotic melanoma was inhibited by 66% in 1 h. In the presence of substrates, effector and cofactors, the radical signal at g = 2.009 was also quenched by 60%; in the absence of substrate, effectors and cofactors, this signal was unaffected. These results indicate that two different free radicals must be present on melanoma RR. One is present in the resting enzyme, and the other is used during catalytic activity. The thiolate-active site of RR from melanoma was inhibited by the new nitrosourea anti-tumour drug fotemustine (IC50 = 10(-4) M as determined from a dose-response study).(ABSTRACT TRUNCATED AT 250 WORDS)
Melanoma Res 1992 Dec
PMID:Ribonucleotide diphosphate reductase from human metastatic melanoma. 133

The 5-year survival rate for malignant melanoma has increased 40% over the last 50 years. During this same time period, the treatment for the disease has not changed significantly, and consists of wide excision of the primary tumour and perhaps regional node dissection. The purpose of this study was to investigate the possible impact of screening/education programs on melanoma survival. In 1987, a multimodality University-based Melanoma Treatment Center was established and programs were instituted for skin cancer screening and Continuing Medical Education (CME) of health care providers. During the last 5 years, 594 patients with newly diagnosed melanoma have been registered at the clinic. The number of patients with localized (stage 1 or 2, negative regional nodes) disease was 516 (85%). For all stages of disease, the 3-year actuarial survival for this screened population was 85%. From the National Cancer Database of 9879 patients registered with melanoma for 1988, 75% had localized disease and the 3-year survival was 76%. There were significant differences noted between the screened Florida population and the nationwide database using an odds ratio statistic. This involved a higher frequency of patients diagnosed with localized disease (odds ratio = 1.89 (1.49-2.40)) and a better survival (odds ratio = 1.79 (1.41-2.27)) in the screened population served by CME-educated community physicians.
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PMID:The effectiveness of skin cancer screening and continuing medical education programs toward increasing the survival of patients with malignant melanoma. 134 Dec 74

The Scottish Melanoma Group (SMG) was established in 1979 to assess mortality from and incidence, features, pathological data, and management of cutaneous malignant melanoma in Scotland. Incidence during the first five years and five-year survival have already been reported. We now have data about incidence and mortality over eleven years in relation to anatomical site and pathological types. From 1979 to 1989, 1354 male and 2459 female patients with primary cutaneous malignant melanomas were first diagnosed in Scottish residents. The incidence rate per 100,000 population per year has increased from 3.4 in 1979 to 7.1 in 1989 for men, and from 6.6 to 10.4 for women. The overall increase over eleven years is 82% (7.4% per year). The greatest rates of increase are seen in lesions of the superficial spreading histogenetic type, arising on the female leg and the male trunk. Following public education programmes started in 1985, the proportion of all melanomas less than 1.5 mm thick has shown a sustained and significant increase. Mortality data for 1661 patients for whom a minimum of five-year follow-up is available shows five-year survival of 71.6% overall (77.6% for women, 58.7% for men). The survival advantage for women persists when appropriate statistical adjustment is made for thickness, ulceration, and histogenetic type. These data are useful in designing public education programmes aimed at both primary and secondary prevention of melanoma and in auditing changes in trends that might result from such education.
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PMID:Cutaneous malignant melanoma, Scotland, 1979-89. The Scottish Melanoma Group. 134 7

Five clones derived from the same human malignant melanoma lesion were studied for their susceptibility to killing by human monocytes activated by exposure to interferon (IFN)-gamma and lipopolysaccharide. Melanoma clones were heterogeneous in their susceptibility to human monocyte cytotoxicity, with one clone (2/21) exhibiting extremely low levels of lysis. The different levels of susceptibility to monocyte cytotoxicity were not accounted for by susceptibility or resistance to monokines [tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6] because: (a) these effector molecules had little (TNF) or no (IL-1 and IL-6) cytolytic activity under these conditions; and (b) anti-TNF antibodies had marginal effects on cytotoxicity. Monocytes bound less to resistant than to susceptible melanoma cells. Monocyte-resistant 2/21 melanoma cells expressed substantially lower levels of ICAM-1 and VLA-4 than susceptible cells. Anti-CD18 and, to a lesser extent, anti-ICAM-1 mAb inhibited binding and cytotoxicity of human monocytes on malignant melanoma whereas anti-VLA-4 had no inhibitory action. Transfection of the ICAM-1 gene under the control of a constitutive promotor resulted in high levels of expression of ICAM-1 in 2/21 melanoma cells and, concomitantly, in augmented susceptibility to activated monocyte cytotoxicity. The augmented killing of ICAM-1 transfected 2/21 cells was inhibited by anti-ICAM-1 mAb. These results demonstrate that the CD18-ICAM-1 adhesion pathway can play an important role in the expression of human monocyte cytotoxicity on melanoma target cells and that heterogeneity in expression of ICAM-1 can underlie differences in susceptibility to tumoricidal activity.
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PMID:Heterogeneous susceptibility of human melanoma clones to monocyte cytotoxicity: role of ICAM-1 defined by antibody blocking and gene transfer. 135 29

Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma. 135 3


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