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)

Treatment of exponentially proliferating melanogenic Harding-Passey melanoma cells in monolayer culture (HPM-73 line) with a single dose of X-irradiation (up to 8 Gy) or continuously (for several weeks) with L-3,4-dihydroxyphenylalanine (L-Dopa) up to 5 X 10(-4) M resulted in a dose-dependent inhibition of cell proliferation, but not in death of all cells. Actually, 8 Gy-irradiated or L-Dopa (2 X 10(-4) M)-treated cultures finally reached the cell number and cell density of controls. However, a combination of a single dose of radiation (8 Gy) followed by L-Dopa (2 X 10(-4) M)-treatment resulted in destruction of all cells. Melanin formation was stimulated by L-dopa-treatment or X-irradiation, and was further elevated by the combined application of radiation and L-Dopa-exposure. Whether the effects of exogenously applied L-Dopa, an intermediary metabolite of melanin synthesis, are due to the conversion to growth-inhibitory metabolites (quinones, radicals, etc.) inside or outside the cell, was discussed. The latter might result from release (due to membrane damage or cell disintegration) of tyrosinase or/and melanosomes into the culture medium with the consequence of extracellular synthesis of potentially cytotoxic metabolites from medium substrates. Further, endocytosis of exogenous melanosomes and tyrosinase with potentially harmful effects is feasible. An application of such a combination therapy of melanoma to clinical medicine should be considered.
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PMID:Augmentation by L-dopa of growth inhibition and melanin formation of X-irradiated Harding-Passey melanoma cells in culture. 340 51

Synthetic eumelanin prepared by autooxidation of D,L-DOPA causes DNA strand breaks, as determined by alkaline elution after cell lysis with detergent and proteolysis, in B16CL4 mouse melanoma cells. The melanin is toxic to the cells in the range of doses that causes strand breaks. When the melanin was incubated with the cells at 37 degrees C in tissue culture medium, it was maximally effective after 15 to 20 min at causing strand breaks in the DNA. The extent of damage is concentration dependent, but the effect plateaus at 1 mg/ml. The nature of the interaction of the cellular DNA with melanin is consistent with strand breaks, not DNA-DNA crosslinks. The strand break damage is repaired, even in the continued presence of melanin, but repair is more rapid if the cells are washed and the melanin is removed. The form of the melanin is important for obtaining the effect. Sonication for 3 min abrogates the effect to a considerable extent, and repeated cycles of sonication can completely destroy the activity. Lost activity returns slowly with storage at 4 degrees C. Melanin is more effective at damaging DNA in a protein-free medium. It is also DNA-damaging at 4 degrees C, but less so than at 37 degrees C. Preliminary studies indicate that the strand breaks caused by melanin are additive with those caused by ionizing radiation. The extent of DNA strand breaks and alkali-labile sites caused by several other melanins was also determined. Some melanins did not cause frank strand breaks, but were active in causing alkali-labile sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Eumelanin causes DNA strand breaks and kills cells. 350 74

Levodopa-carbidopa has been widely used in the treatment of Parkinson's disease. We are currently investigating the effectiveness of this combination for the treatment of patients with advanced malignant melanoma. As part of this study, we have examined the effects of this combination on the phytohemagglutinin-induced transformation of human lymphocytes, isolated from patients with malignant melanoma prior to undergoing treatment. Levodopa, as well as carbidopa and 3 additional levodopa synthetic analogs, inhibited the transformation of phytohemagglutinin-stimulated DNA synthesis at pharmacologically attainable levels. These results confirm our earlier preclinical observations suggesting that catechols have profound intracellular metabolic effects in a variety of cells other than melanoma cells. It is possible that some of the effects of catechols in other diseases might also be mediated by similar intracellular metabolic effects, and effects on human melanoma might be mediated in part through effects on the immune system. We are currently awaiting introduction of synthetic catechols, including 3,4-dihydroxybenzylamine (NSC 263475), to extend these observations to our clinical studies in patients with advanced metastatic disease.
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PMID:Inhibition of transformation by levodopa-carbidopa in lymphocytes derived from patients with melanoma. 357 25

L-3,4-Dihydroxyphenylalanine (L-dopa) and its structural analogs are known to be potently cytotoxic to melanoma cells. We examined the effects of cysteinylcatechols and related compounds, which were newly synthesized as cysteinyl derivatives of L-dopa, on the growth of human melanoma cells in vitro, and their actions were compared with those of L-dopa. 4-S- and 3-S-Cysteinylcatechols showed significantly more potent cytotoxicity to melanoma cells than did L-dopa, and 2-S-cysteinylhydroquinone was next to the catechols in potency. The mechanism of action may involve interaction with the melanocyte-specific enzyme, tyrosinase, for which the cysteinylcatechols could become a better substrate than L-dopa itself. 4-S-Cysteaminylphenol was almost comparable to L-dopa in cytotoxicity, suggesting that this phenol might be oxidized to the corresponding catechol by tyrosinase within the melanoma cells.
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PMID:The cytotoxicity of cysteinylcatechols and related compounds to human melanoma cells in vitro. 357 26

Malignant melanoma cells possess a unique biochemical pathway that converts L-3,4-dihydroxyphenylalanine (L-dopa) to the biopigment melanin. Selective cytotoxic incorporation of exogenous L-dopa into melanoma cells in vivo may provide a means of designing specific chemotherapeutic agents useful in the treatment of this disease. Using the Harding-Passey murine melanotic tumor model, a preferential uptake of [3H]L-dopa by the tumor was characterized. Following pretreatment of the tumor-bearing mice with nonradioactive L-dopa, a significant enhancement (p less than 0.01) of [3H]L-dopa incorporation and retention into melanoma for a period of 24 h was observed, when compared with the concomitant tissue distribution and clearance of radioactivity in the control animals. This finding suggests that by initial pretreatment of melanoma with nonradioactive L-dopa, the subsequent selective accumulation of [3H]L-dopa in tumor may provide a useful tool in testing new modalities of therapy in malignant melanoma.
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PMID:Pretreatment effects on the uptake/retention kinetics of L-dopa in Harding-Passey melanoma. 374 66

In 19 patients with malignant melanoma of the choroid and 11 controls 20 different metabolic parameters of melanin and melatonin metabolism in urine were examined by high-pressure liquid chromatography (HPLC). Significant differences were found in DOPA, DOPAC, MHPG, alpha-keto-glutaric acid, pseudo-uridine, serotonin, OH-tryptophan and homovanillic acid.
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PMID:[HPLC detection of pathologic metabolites of melanin and melatonin metabolism in the urine in malignant melanoma of the choroid]. 376 75

We have evaluated the chemotherapeutic potential of 2,4-dihydroxyphenylalanine, a targeted prodrug that can be hydroxylated by tyrosinase (monophenol monooxygenase, EC 1.14.18.1) within melanoma cells to form the cellular toxin 2,4,5-trihydroxyphenylalanine (6-hydroxydopa). 2,4-Dihydroxyphenylalanine proved to be cytotoxic to both B-16 and Cloudman melanoma cells in vitro. The immediate effects of 2,4-dihydroxyphenylalanine included inhibition of DNA, RNA, and protein syntheses. In contrast, no decrease in macromolecular synthesis or viability was seen against cultures of MJY-alpha mammary tumor or L-1210 leukemia, two cell types that do not contain tyrosinase. Within the melanoma cultures, greater cytotoxicity was seen against melanotic (tyrosinase-containing) cells than against amelanotic (tyrosinase-lacking) cells. The cytotoxicity of 2,4-dihydroxyphenylalanine was blocked by 1-phenylthiourea, an inhibitor of tyrosinase. These results show that 2,4-dihydroxyphenylalanine is toxic to melanoma cells and that activation of 2,4-dihydroxyphenylalanine requires the presence of tyrosinase.
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PMID:In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells. 392 68

The oxidation of 5,6-dihydroxyindole by tyrosinases from mushroom, Harding-Passey melanoma, bovine eye and Bufo bufo embryo has been investigated. The apparent Km values for this substrate were measured and found to be of the same order of magnitude as those for L-tyrosine and L-3,4-dihydroxyphenylalanine, as reported in the literature (5 x 10(-4) M). The 5,6-dihydroxyindole oxidases of mushroom and T4 melanoma isozyme are sensitive to phenylthiourea, while, on the other hand, those from crude preparations of bovine and B. bufo tyrosinases are not sensitive to the inhibitor in an evident manner. The action of some indole derivatives on the 5,6-dihydroxyindole oxidase of mushroom has also been investigated.
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PMID:5,6-Dihydroxyindole oxidation by mammalian, mushroom and amphibian tyrosinase preparations. 392 6

Some enzyme activities and metabolic features of the black Ma melanotic, brown MI melanotic and Ab amelanotic melanomas of hamster were investigated. The activities of hexokinase and phosphofructokinase were similar in all three melanomas, the activity of NAD-dependent glycerol-3-phosphate dehydrogenase was higher in the amelanotic melanoma and that of pyruvate kinase and lactate dehydrogenase were slightly lower in MI than in the other tumors. The activities of citrate synthase, succinate dehydrogenase and malate dehydrogenase were higher in the Ma and MI melanotic melanomas than in the Ab amelanotic melanoma. The rate of labeled CO2 production from 6-14C-glucose, 1,5-14C-citric acid and U-14C-glutamine was about 2 times higher in melanotic melanomas than in amelanotic one, while no significant differences among the three melanomas were found in respect to 1-14C-glucose and U-14C-glycerol-3-phosphate. The production of 14CO2 was much higher from 1-14C-glucose than from 6-14C-glucose in all the melanomas studied. L-DOPA stimulated the production of 14CO2 from 1-14C-glucose much stronger in the Ma and MI melanomas than in the Ab melanoma. In none of the tumors the incorporation from 6-14C-glucose to CO2 was affected by L-DOPA. It is postulated that oxidation of glucose via the pentose phosphate cycle is involved in melanogenesis.
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PMID:Metabolic characterization of three hamster melanoma variants. 406 92

Peroxide-dependent enzymic oxidation of tyrosine to dopachrome and melanin was demonstrated in cell-free melanoma homogenates. Histochemical methods for distinguishing peroxidase activity from aerobic dopa (3,4-dihydroxyphenylalanine) oxidase activity are not reliable with cell-free preparations. Therefore the presence of peroxidase activity in such preparations precludes assay of cresolase activity of mammalian ;tyrosinase'.
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PMID:Peroxidatic oxidation of tyrosine to melanin in supernatant of crude mouse melanoma homogenates. 444 86


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