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)

Tyrosine countertransport was used to demonstrate the existence of a carrier system for neutral amino acids in the lysosomal membrane of FRTL-5 thyroid cells. In addition to tyrosine, the carrier system recognized the neutral amino acids leucine, histidine, phenylalanine, and tryptophan. Cystine and lysine, amino acids for which a lysosomal carrier system has been demonstrated, showed no competition with tyrosine for countertransport. The tyrosine system showed stereospecificity and cation independence. It did not require an acidic lysosome or the availability of free thiols. The apparent Km for tyrosine was approximately 100 microM; the energy of activation of the system was approximately 9.7 kcal/mol. This new lysosomal membrane carrier system for neutral amino acids resembles the plasma membrane L system in 3T3 Chinese hamster ovary cells and melanoma B-16 cells.
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PMID:Characteristics of a lysosomal membrane transport system for tyrosine and other neutral amino acids in rat thyroid cells. 378 56

Treatment with the drug combination of levodopa methylester and benserazide, supplemental ascorbate, and dietary deficiencies of tyrosine and phenylalanine more than doubled the median survival time of female (C57BL/6 X DBA/2)F1 mice bearing B16 melanoma tumors. The mechanism for this antitumor effect was not well defined. This study was designed to test the hypothesis that the antitumor activity of levodopa methylester and ascorbate against B16 melanoma is related to the generation of free radicals of oxygen, which peroxidize lipid constituents of cell membranes leading to cell death. As an indication of lipid peroxidation, the individual and combined effects of drug treatment and ascorbate supplementation on host and tumor malondialdehyde levels were examined in mice fed one of three test diets (commercial, purified, or deficient) containing decreasing amounts of tyrosine and phenylalanine. Malondialdehyde levels were increased in the livers of all untreated tumor-bearing mice, which suggests that the tumor alters host antioxidant defenses. Drug treatment and ascorbate supplementation alone and in combination increased hepatic malondialdehyde levels inversely to the amounts of tyrosine and phenylalanine in the diet, and the effects of drug and ascorbate on malondialdehyde levels were additive. Plasma levels remained unchanged by drug treatment, ascorbate supplementation, or tumors in mice fed the commercial or purified diets. Higher levels were observed only in tumor-bearing mice fed the deficient diet and given both drug treatment and ascorbate supplementation. Changes in tumor malondialdehyde levels generally correlated with the effects of the drug and ascorbate on survival time of mice bearing B16 melanoma. Tumors from mice fed the commercial diet accumulated little malondialdehyde, and therapy was relatively ineffective in this dietary group. In mice fed purified or deficient diets, drug treatment and ascorbate supplementation alone increased survival and tumor malondialdehyde levels, but the level of peroxidation in mice receiving the ascorbate supplementation was low compared to its greater antitumor effect on B16 melanoma. Although ascorbate enhanced the peroxidative activity of the drug on B16 melanoma tumors, the effects of the drug and ascorbate on malondialdehyde levels were not additive. Ascorbate enhanced survival of tumor-bearing mice that were fed the deficient diet and that were treated with drug, which indicated that ascorbate supplementation acted via other mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of peroxidation in murine melanoma by dietary tyrosine-phenylalanine restriction, levodopa methylester chemotherapy, and sodium ascorbate supplementation. 386 1

A melanoma-associated oncofetal antigen, gp87 (a p97-like molecule), defined by the monoclonal antibody (MoAb) 140.240 has been purified to homogeneity from the spent medium of cultured melanoma cells by a two-step immunoadsorbent procedure. The first immunoadsorbent step using glutaraldehyde-insolubilized MoAb 140.240 (ascites fluid) resulted in a 13-fold enrichment with 93% recovery in the bound material. In the second immunoadsorbent step constructed by the purified IgG2a of MoAb 140.240 (culture fluid) coupled to CNBr-activated Sepharose 4B the bound material from the first step was further purified resulting in a 330-fold purification with 90% recovery. SDS-polyacrylamide gel electrophoretic analysis of the final purified material revealed a single band migrating as a polypeptide with an approximate molecular weight of 87 Kd, consistent with the size of the molecule immunoprecipitated by MoAb 140.240 from lysates of radiolabelled melanoma cells. Preliminary amino acid analysis indicates a particularly high proportion of phenylalanine in gp87. We have also compared gp87 with two well defined antigens, HLA-A,B,C (integral membrane protein) and "94K" melanoma/carcinoma-associated antigen (peripheral membrane protein) with respect to antigen extractability from melanoma cells using phosphate-buffered saline, 0.1 M urea, 3 M NaCl, or nonionic detergent (NP-40). The results showed that whereas 94K antigen was extractable by each of the four different solutions, gp87, similar to HLA-A,B,C antigens, could only be extracted with NP-40, strongly suggesting that gp87 is an integral melanoma cell component.
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PMID:Immunopurification, characterization, and nature of membrane association of human melanoma-associated oncofetal antigen gp87 defined by monoclonal antibody 140.240. 388 78

The present study characterizes the biological response of a cloned human melanotic melanoma cell line (NEL-M1) to glucocorticoid treatment. Scatchard analysis of the binding of [3H]-triamcinolone acetonide to the glucocorticoid receptor showed a binding capacity of 170 fmol/mg protein and a dissociation constant (KD) of 1.76 X 10(-9) M. When the 3H-labeled cytosol was warmed to 25 degrees C for 30 min and then incubated with DNA-cellulose at 4 degrees C for 45 min, 32% of the specific glucocorticoid-receptor complexes were bound to DNA-cellulose. Additional studies showed that when NEL-M1 cells were cultured for 72 h with 1 X 10(-7) M triamcinolone acetonide, a 36% reduction in cellular growth was observed compared to the control cultures. The calculated population doubling time for the control cells was 17.5 h compared to 20.3 h for the triamcinolone acetonide-treated cells. Analysis of the effect of triamcinolone acetonide on macromolecular synthesis revealed that, over a 24-h incubation period, triamcinolone acetonide (a) inhibited [3H]thymidine incorporation by 51%; (b) increased the incorporation of the melanin precursor, L-3,4-dihydroxy[3H]phenylalanine, by 59%; and (c) had essentially no effect on [3H]leucine or [3H]uridine incorporation. During this same incubation period, triamcinolone acetonide inhibited [3H]glucose uptake by 19%. Further studies using synchronized NEL-M1 cells clearly show that the earliest detectable action of triamcinolone acetonide was the inhibition [3H]thymidine incorporation during the S phase of the cell cycle. Thus, these findings show that the human melanoma cell line, NEL-M1, is biologically responsive to glucocorticoid treatment. Continued studies using NEL-M1 cells may eventually lead to ascertaining the exact mechanism by which glucocorticoids regulate DNA synthesis.
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PMID:Suppression of DNA synthesis in NEL-M1 human melanoma cells by triamcinolone acetonide. 391 42

Previous studies indicate dietary phenylalanine and tyrosine restriction may be of value in managing advanced cancer patients. To further evaluate this approach, we performed a 60-day study in which four patients with advanced malignant melanoma received formula diets via nasogastric tube containing only 8 mg total phenylalanine and tyrosine per kg lean body mass per day. Two of three patients completing elemental balance studies were in negative nitrogen, potassium, and phosphorus balance, suggesting an essential nutrient deficiency. Three patients tolerated the diet well, but one was non-compliant. Although no serious toxicity developed, serum albumin, total iron binding capacity and cholesterol significantly decreased (p less than 0.01) in the three complaint patients. Fasting plasma phenylalanine and tyrosine values did not significantly change during the study, but two-hour postprandial plasma phenylalanine and tyrosine concentrations fell below normal and were significantly lower than preprandial levels (p less than 0.01). There were no tumor responses.
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PMID:The effect of a phenylalanine and tyrosine restricted diet on elemental balance studies and plasma aminograms of patients with disseminated malignant melanoma. 396 27

During the period from February to October 1983, 21 patients with malignant melanoma of the extremities were treated by hyperthermic regional isolated perfusion with L-phenylalanine mustard (melphalan). The melphalan dose for each patient was determined by the tissue volume of the perfused region, using a dose of 10 mg/l perfused tissue. Despite an average increase of melphalan dosage of 18% above the maximum for iliac perfusions recommended in the literature, no increase in toxic tissue reactions was observed after hyperthermic iliac perfusions. The same dose of 10 mg/l perfused tissue was used in hyperthermic axillary perfusions, resulting in an average decrease of melphalan dosage of 14% below the minimum recommended in the literature. By applying a constant dose per unit tissue volume, a standardization of treatment is achieved. This excludes variations like body weight, age, type of complexion, and hair color, which so far have determined dosimetry.
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PMID:Dosimetry of cytostatics in hyperthermic regional isolated perfusion. 396 66

alpha-Melanocyte-stimulating hormone (alpha-melanotropin; alpha-MSH) is a linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) that reversibly darkens amphibian skins by stimulating melanomsome (pigment granule) dispersion within melanophores. By using a number of in vitro melanocyte assays, we have examined the conformational requirements for alpha-MSH activity. Synthesis of [half-Cys4,half-Cys10]-alpha-MSH, a cyclic, conformationally restricted, "isosteric" analogue of alpha-MSH, provided a melanotropin with a potency greater than 10,000 times that of the native hormone in stimulating frog (Rana pipiens) skin darkening. The cyclic analogue also showed substantially prolonged activity relative to the native hormone. [half-Cys4,half-Cys10]-alpha-MSH was approximately 30 times more potent than alpha-MSH in stimulating lizard (Anolis carolinensis) skin melanophores in vitro. By using a cell-free Cloudman S-91 mouse melanoma plasma membrane preparation, we found the cyclic analogue to be approximately 3 times as potent as the native hormone in stimulating adenylate cyclase activity. These results provide insight into the conformational requirements for biological activity of alpha-MSH, and the comparative conformational requirements of alpha-MSH at a number of pigment cell receptors.
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PMID:[half-Cys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: a cyclic alpha-melanotropin exhibiting superagonist biological activity. 628 85

We have prepared several alpha-melanotropin (alpha-MSH) analogues with tyrosine substituted for methionine at the 4-position and determined their melanotropic activities on the frog (Rana pipiens), lizard (Anolis carolinensis) and S-91 (Cloudman) mouse melanoma adenylate cyclase bioassays. The potencies of Ac-[Tyr4]-alpha-MSH4-10-NH2 and Ac-[Tyr4]-alpha-MSH4-11-NH2 were compared with alpha-MSH and with their corresponding methionine and norleucine substituted analogues. The Tyr-4 analogues were found to be less active than the Nle-4 analogues on both the frog and lizard assays. Ac-[Tyr4]-alpha-MSH4-10-NH2 was found to be less active than Ac-[Tyr4]-alpha-MSH4-11-NH2 on the lizard bioassay, but more active than the longer fragment on the frog skin assay. Ac-[Tyr4]-alpha-MSH4-10-NH2 exhibited extremely prolonged biological activity on frog skin, but not on lizard skin, while the melanotropic activity of Ac-[Tyr4]-alpha-MSH4-11-NH2 was rapidly reversed on both assay systems. The increased potency of Ac-[Tyr4]-alpha-MSH4-10-NH2 over Ac-[Tyr4]-alpha-MSH4-11-NH2 on frog melanocytes may be related to the fact that the shorter 4-10 analogue exhibits prolonged biological activity. Interestingly, it was found that both Tyr-4 analogues were partial agonists on the mouse melanoma adenylate cyclase bioassay, and stimulated the enzyme to only about 50% of the maximal activity of alpha-MSH. We reported previously that replacement of L-Phe-7 by its D-enantiomer in [Nle4]-alpha-MSH and its Nle-4 containing analogues resulted in peptides with increased potency and in some instances prolonged activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative biological activities of potent active-site analogues of alpha-melanotropin. Effect of tyrosine substitution at position-4. 633 85

Biocytin derivatives of a superpotent analogue of alpha-melanotropin, [Nle4,D-Phe7]-alpha-MSH, were prepared. [N alpha-Bct-Ser1, Nle4,D-Phe7]-alpha-MSH and [12-Bct-N alpha-dodecanoyl-Ser1,Nle4,D-Phe 7]- alpha-MSH were synthesized by solid-phase techniques, and the coupling of biotin and 12-aminododecanoic acid was achieved through their succinimido esters. These melanotropins possessed almost identical actions to [Nle4,D-Phe 7]- alpha-MSH as determined by several melanocyte bioassays. Both biocytin derivatives were highly potent agonists and exhibited prolonged biological activity as determined in the frog and lizard skin bioassays. Both biotinylated peptides were at least equipotent to alpha-MSH in stimulating Cloudman S91 mouse melanoma tyrosinase activity. The analogues were resistant to inactivation by alpha-chymotrypsin.
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PMID:Synthesis and biological actions of highly potent and prolonged acting biotin-labeled melanotropins. 643 88

A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters of N-alpha-[(2-nitro-1-imidazolyl)acetyl]-L-phenylalanine and N-alpha-[2-nitro-1-imidazolyl)acetyl]-L-tyrosine were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. The sensitizer enhancement ratios (SER) of these derivatives were 2.2 and 2.3 respectively at 1 mM concentration after 2 hr exposure under hypoxia. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. These agents were cleared from the plasma rapidly with an apparent t 1/2 of 18.8 and 15.6 min respectively. Peak tumor concentration of approximately 217 micrograms/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.
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PMID:Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers. 646 54


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