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)

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.
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PMID:[Study of new antineoplastic antibiotics based on newly discovered action mechanisms]. 619 73

Activities of pyrimidine nucleoside phosphorylase in brain tumors were measured and their relationship to a clinical course of the patients was investigated. Pyrimidine nucleoside phosphorylase is said to exist more quantitatively in malignant tumors such as Sarcoma 180, Ehrlich ascites carcinoma, Walker 256, and hepatoma, and very little in normal tissues. In brain tumors the activities were measured by bioassay and compared to that of Sarcoma 180. When the activity of Sarcoma 180 was expressed to be 100%, those of brain tumors were as follows: ten cases of normal brain less than 8.5; six cases of glioblastoma 39.3 +/- 30.7; five cases of astrocytoma 22.0 +/- 13.8; five cases of meningioma 22.4 +/- 13.7; two cases of oligodendroglioma 8.1 and 11.3; two cases of sarcoma 94.3 and 145.4; chordoma 48.0; ependymoblastoma 3.7; plexus papilloma 22.5; parotid cancer 43.4; ten cases of metastatic brain tumors from lung cancer 61.5 +/- 41.6; two cases from breast cancer 28.0 and 68.8; that from thyroid cancer 10.0; that from gastric cancer 13.5; malignant melanoma 77.2. In 12 cases of gliomas (glioblastoma, astrocytoma, oligodendroglioma) the mean activity was highest in glioblastoma (39.3), followed by astrocytoma (22.0) and oligodendroglioma (9.7). The postoperative survival time became shorter in gliomas with the higher activities. In metastatic brain tumors from lung, breast, and gastric cancer, the average time from the diagnosis of primary cancer to brain metastasis was shorter in cases with high activities and longer in cases with low activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Activities of pyrimidine nucleoside phosphorylase in brain tumors and antitumor effect of 5'-DFUR]. 622 41

N-Phosphonacetyl-L-aspartic acid (PALA) resistance may be due to the ability of tumor cells to utilize preformed circulating pyrimidine nucleosides, thereby overcoming the block of de novo pyrimidine biosynthesis which PALA causes. To test this hypothesis we examined the effects of PALA and nitrobenzylthioinosine (NBMPR) alone and in combination on B16 melanoma cells in vitro using a clonogenic assay and in vivo using growth delay. In medium containing purine and pyrimidine nucleosides at a final concentration of 28 microM, exposure to PALA (100 microM) alone or to NBMPR (10 microM) alone for periods up to 72 hr did not result in any cytotoxicity. However, exposures to PALA (100 microM) plus NBMPR (10 microM) resulted in a decrease in clonogenic survival to 0.011 at 72 hr. In medium without nucleosides, PALA (100 microM) exposure for 72 hr caused a similar decrease in survival to 0.015, whereas NBMPR (10 microM) had no effect on survival. The addition of uridine resulted in a concentration-dependent reversal of the cytotoxic effects of PALA. C57 Bl female mice bearing B16 melanoma were treated intraperitoneally daily for 4 days with PALA, the phosphate of NBMPR (NBMPR-P), or PALA plus NBMPR-P. PALA, 300 mg/kg daily X 4, resulted in a 6-day tumor growth delay but NBMPR-P, 100 mg/kg daily X 4, had no effect. PALA, 150 mg/kg daily X 4, plus NBMPR, 50 or 100 mg/kg daily X 4, resulted in a 6-day tumor growth delay also. These studies demonstrate that: (1) circulating pyrimidine nucleosides are determinants of the cytotoxic effects of PALA; (2) in vitro PALA and NBMPR combine to cause significant cytotoxicity whereas either agent alone has no effect; (3) in vivo the combination of PALA and NBMPR-P results in the same antitumor affect as PALA alone at twice the dose; and (4) due to an increase in animal toxicity, no therapeutic advantage could be demonstrated for the combination over PALA alone in vivo. We conclude that the cytotoxic effect of PALA is modulated by the levels of the preformed circulating nucleosides and that combining PALA with an inhibitor of salvage pyrimidine uptake would not increase the therapeutic efficacy of PALA because of an increase in toxicity.
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PMID:Antitumor activity of N-phosphonacetyl-L-aspartic acid in combination with nitrobenzylthioinosine. 648 65

Cytotoxicity and perturbations of the deoxyribonucleoside triphosphate pools caused by thymidine were studied in thymidine-sensitive and -resistant human tumor cells. Incubation with 1 mM thymidine reduced cell viability by more than 90% in the three sensitive cell lines (two melanomas and one adrenal carcinoma) and reduced the growth rate without decreasing the viability of resistant LO melanoma cells. Thymidine (1 mM) greatly increased the ratio of the deoxythymidine 5'-triphosphate to deoxycytidine 5'-triphosphate pools in the sensitive cells compared to LO cells and also caused larger relative increases in the pool sizes of deoxyguanosine 5'-triphosphate and deoxyadenosine 5'-triphosphate in the sensitive compared to the resistant cells. 3-Deazauridine, known to inhibit synthesis of deoxycytidine 5'-triphosphate and cytidine 5'-triphosphate in other cell lines, potentiated the cytotoxicity of thymidine for thymidine-sensitive BE melanoma and LO cells. In LO cells, 3-deazauridine (50 microM) decreased the intracellular pool of deoxycytidine 5'-triphosphate to the level obtained with 1 mM thymidine. Lower concentrations of deoxycytidine as compared to cytidine were required to protect BE and LO cells against the cytotoxicity of thymidine plus 3-deazauridine. Deoxycytidine also was more effective than was cytidine in preventing loss of cell viability after exposure to thymidine or to 3-deazauridine individually. In these human melanoma cells, ribonucleotide reductase may be a major site of action of thymidine, of 3-deazauridine, and of both drugs in combination. These results indicate that in human tumor cells the cytotoxic effect of thymidine correlates with greater perturbations of the pyrimidine deoxyribonucleoside 5'-triphosphate pools and that thymidine and 3-deazauridine, which independently reduce the intracellular levels of deoxycytidine 5'-triphosphate, act synergistically against human tumor cells.
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PMID:Cytotoxic and biochemical effects of thymidine and 3-deazauridine on human tumor cells. 672 92

Thiouracil is a thiol-containing pyrimidine that is selectively incorporated into cells that synthesize melanin. In an effort to delineate further the specificity and dynamics of uptake, we injected thiouracil labeled with radioactive carbon into S91 melanoma-bearing mice; biopsy specimens were taken of the tumors and organs at various time intervals thereafter. The data showed a substantial uptake of thiouracil by the melanomas, with peak uptake occurring at 24 hours. All other organs examined showed only minor amounts of radioactivity, which probably reflected the presence of thiouracil in the blood perfusing these tissues. Because of its incorporation into melanomas, the use of radioactive thiouracil has potential as a marker for tumor growth, as a diagnostic tracer compound, and as a carrier for chemotherapeutic agents.
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PMID:Detection of melanomas. Approach with radiolabeled false precursors of melanin synthesis. 683 35

Uridine (Urd) phosphorylase and Urd kinase activities were examined in 4 human tumor types including melanoma and human and mouse melanoma cell lines. Urd phosphorylase activity in melanoma tumor specimens was higher than in specimens of colon, ovarian, and breast tumors. Urd kinase activity levels were similar in the 4 tumor types. In 3 human melanoma cell lines examined, Urd phosphorylase activity was markedly greater than in mouse B16 melanoma cells, while Urd kinase activity did not differ appreciably in the human and mouse cell lines. Urd phosphorylase activity in crude extract preparations from different melanoma cell lines showed similar substrate affinity and sensitivity to 1-(2'-deoxy-beta-D-glucopyranosyl)-thymine, a specific inhibitor. The high Urd phosphorylase activity found in melanoma tumor tissue may be exploited in the treatment of malignant melanoma with antipyrimidine agents. Cultured human melanoma cells retain this biochemical characteristic and may serve as appropriate in vitro models for the human tumor in studies concerning pyrimidine metabolism.
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PMID:High uridine phosphorylase activity in human melanoma tumor. 688 21

A human melanoma cell line (MM253) was found to be sensitive to ultraviolet (UV) radiation, having a Do of 1.0 J/M2 when cloned on plastic culture dishes and a Do of 2.3 J/m2 when cloned in agar. These figures are much lower than those obtained for all other human melanoma cell lines studied in this laboratory (Do of 32-40 J/m2) and demonstrate that MM253 is unusually UV sensitive. The increased level of UV sensitivity in MM253 is not due to a reduced capacity for excision of pyrimidine dimers, repair of DNA single-strand breaks or elongation of newly-synthesized DNA strands when comparison is made with a UV-resistant melanoma cell line.
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PMID:Sensitivity and resistance of human melanoma cells to ultraviolet radiation. 729 23

N-Phosphonacetyl-L-aspartic acid (PALA) is new synthetic antimetabolite which inhibits de novo pyrimidine biosynthesis. Its significant activity against Lewis lung carcinoma, B16 melanoma, and glioma 26 suggested that it might be useful in the treatment of human solid tumors. Phase I trials revealed that dose-limiting toxicity included skin reactions, diarrhea, and stomatitis. Pharmacologic studies demonstrated rapid renal excretion of more than 70% of the unmetabolized drug in 24 h. Peak plasma levels correlated with dose of PALA administered. Partial responses to PALA were seen in one patient with melanoma, one with chondrosarcoma, and one with colon carcinoma. The potential for PALA's use in combination chemotherapy, particularly with 5-fluorouracil, is discussed.
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PMID:An overview of the clinical pharmacology of N-phosphonacetyl-L-aspartate (PALA), a new antimetabolite. 744 50

Mutations in the ras oncogene are detected with a high frequency in non-melanoma skin cancer. Approximately half of the squamous-cell carcinomas (SCC) and one third of the basal-cell carcinomas (BCC) carry mutations at the second position of Ha-ras codon 12 (GGC to GTC), whereas mutations in Ki-ras codon 12 occur less frequently. Since the mutations in the Ha-ras and Ki-ras oncogenes are located opposite potential pyrimidine dimer sites (C-C), it is likely that the mutations are induced by ultraviolet radiation present in sunlight. We studied the capacity of ultraviolet B (UVB) light to induce base-pair changes in Ha-ras codons 11 and 12 in human skin fibroblasts. UVB induced mostly C to T and G to A transitions and C to A and G to T transversions. The base-pair change with the highest relative abundance was C to T in the middle position of codon 11 followed by (in diminishing relative abundance) C to A in the middle position of codon 11, G to A and G to T in the middle position of codon 12. The C to T and G to A transitions are compatible with pyrimidine photodimers as pre-mutagenic lesions, whereas the C to A and G to T transversions could be generated due to the formation of 8-hydroxyguanine, which is the major oxidation product of guanine. The relative abundance of mutations induced by UVB in Ha-ras codons 11 and 12 does not correlate with mutations observed in the DNA from non-melanoma skin cancer, where the G to T transversion in the middle position of codon 12 is selected.
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PMID:Ultraviolet-B-light-induced mutagenesis of C-H-ras codons 11 and 12 in human skin fibroblasts. 755 42

Mutations in the p53 tumor suppressor gene are detected in approximately half of non-melanoma skin cancers. The type of base-pair changes observed strongly suggests solar radiation as the causative mutagen. Mutations are distributed nonrandomly and form moderate hotspots. We studied the capacity of ultraviolet B light (UVB, 280-320 nm) to induce base-pair changes into the p53 exon 7 sequence extending from nt 14067 to 14075 in human skin fibroblasts. This sequence contains hotspot codon 248. UVB induced mostly C-->A and G-->T transversions. The base-pair change with the highest relative abundance was C-->A in the first position of codon 250 (CCC-->ACC), followed by (in diminishing relative abundance) G-->T in the third position of codon 249 (AGG-->AGT), C-->A in the first position of codon 248 (CGG-->AGG), and C-->A in the third position of codon 247 (AAC-->AAA). The C-->T transition in the third position of codon 247 (AAC-->AAT) occurred with moderate efficiency. These base-pair changes are compatible with pyrimidine photodimers as premutagenic lesions, but they could also form opposite 8-hydroxyguanine, which is the major oxidation product of guanine. No evidence was obtained for the presence of tandem double CC-->TT transitions in the untranscribed strand at codons 247/248 and 250. The relative abundance of mutations induced by UVB in the p53 sequence extending from codon 247 to 250 in human fibroblasts does not correlate with mutations observed in the DNA from non-melanoma skin cancer. This lack of correlation suggests that the mutability of this p53 sequence at the DNA level plays only a minor role in the pathogenesis of non-melanoma skin cancer in humans.
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PMID:Ultraviolet B light-induced mutagenesis of p53 hotspot codons 248 and 249 in human skin fibroblasts. 806 78


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