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)

Serum removal from the media of serial monolayer cultures of the Harding-Passey melanoma during an incubation period of 3 days resulted in an exponentially declining DNA synthesis rate (measured by the incorporation of [14C]thymidine) and in an inhibition of cell proliferation. Protein synthesis, as measured by the incorporation of radioactive leucine, was less affected than DNA synthesis. Incubation in serum-free culture medium resulted in significant rises of tyrosinase activity and cellular melanin content. Addition of dibutyryl adenosine 3':5' monophosphate (Bu2cAMP, 5X10(-4) M) and theophylline (5X10(-4) M) to serum-free cultures caused a further striking increase of tyrosinase activity and melanin formation, while treatment of serum containing cultures with Bu2cAMP and theophylline showed only a slight rise in melanogenesis. It is suggested that these stimulatory effects are mediated by an increased intracellular cAMP level, since a correlation between the degree of melanogenesis and cellular cAMP content was indicated. Treatment of serum-free or serum-containing cultures with the phosphodiesterase inhibitor theophylline (5X10(-4)--10(-3)M) alone revealed only a slight enhancement (about 20%) of melanogenesis. Because augmentation of melanogenesis by serum-free medium alone or together with Bu2cAMP and theophylline was prevented by cycloheximide (or actinomycin D), de novo protein synthesis seems to be required for these stimulatory effects.
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PMID:Stimulation of tyrosinase activity and melanin formation of cultured melanoma cells by serum deprivation alone or in combination with dibutyryl cyclic AMP and theophylline. 19 88

It was shown on albino mice that when DOPA-3H (20 muCi/mouse) was administered before nonradioactive DOPA (1 mg/mouse) tritium accumulation in the tissue of Harding-Passi's melanoma of these mice proved to increase. Melanoma radioactivity in this experimental group was double that in the tumour tissue of the animals to which DOPA-3H alone was administered. Examination of the adenylate cyclase, phosphodiesterase activity and of the level of cAMP in melanoma of mice 2 hours after DOPA administration (1 mg/mouse) showed accumulation of cAMP and an increase in the phosphodiesterase activity; as to adenylate cyclase activity--it fell. It is suggested that DOPA realizes its effect not only as melanin precursor, but also through the cAMP system, influencing the melanogenesis enzymes activity.
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PMID:[Regulatory role of DOPA and components of the cyclic adenosine-3',5'-monophosphate system]. 20 73

Theophyllin, an inhibitor of cAMP-degrading phosphodiesterase, stimulates melanin biosynthesis in cultures of RPMI 3460 hamster melanoma cells. Although theophylline does produce an initial transient elevation of intracellular cAMP levels, long-term treatment with theophylline produces a significant decrease in cAMP content. There is an inhibition of the theophylline stimulation by dibutyryl-cAMP; this is apparently caused by interference of dibutyryl-cAMP with the uptake and incorporation of theophylline, as shown by experiments with 3H-theophylline. An alternative theory is that theophylline, being a methylxanthine compound, is metabolized by the cell and possibly causes melanotic stimulation by becoming incorporated into cellular nucleic acids or by altering the normal nucleic acid metabolism. The following observations are consistent with this theory: (u) 3H-theophylline was incorporated into both trichloroacetic acid (TCA)-soluble and TCA-insoluble cell fractions; most of the insoluble label became soluble after digestion with ribonuclease and deoxyribonuclease. (2) These nuclease digests of the 3H-theophylline-labeled TCA-insoluble cell fractions contained 3H-labeled material that chromatographed differently from normal nucleotides on ion exchange thin layer sheets. (3) The acid-soluble pool of 3H label disappeared rapidly while both the insoluble label and the induction of melanogenesis remained stable for 50 hr after the removal of exogenous 3H-theophylline.
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PMID:Theophylline incorporation into the nucleic acids of theophylline-stimulated melanoma cells. 21 85

Theophylline, a phosphodiesterase inhibitor, was found to be a potent stimulator of melanogenesis in the RPMI 3460 hamster melanoma cell line. This stimulation was greater than that caused by either dibutyryl cyclic AMP (db-cAMP) or another phosphodiesterase inhibitor, papaverine. Theophylline and db-cAMP treatments also produced strikingly different morphologies in the monolayered cells. The theophylline effect on melanogenesis was diminished by db-cAMP, whereas simultaneous treatment of cells with db-cAMP and papaverine produced greater stimulation of melanotic activity than either agent acting alone. Theophylline, therefore, may have phenotypic effects that are at least partially independent of phosphodiesterase inhibition. Theophylline stimulated melanin biosynthesis, as measured by rates of 2-[2-14C] thiouracil incorporation, and also caused an increase in the level of tyrosinase (EC 1.10.3.1) activity. This melanotic stimulation was prevented by the presence of cordycepin or cycloheximide. Theophylline inhibited DNA synthesis and mitosis in the melanoma cell cultures but stimulated protein synthesis. However, inhibition of proliferation and the first appearance of induced melanotic activity did not bear an immediate direct relationship to one another.
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PMID:Stimulation of melanotic expression in a melanoma cell line by theophylline. 81 64

The rationale for melanoma-specific antitumor agents containing phenolic amines is based in part on the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. The phenolic amine compounds 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) inhibited in situ thymidylate synthase activity in pigmented melanoma cell lines but had little or no effect on nonpigmented and nonmelanoma cell lines. Theophylline, a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, increased tyrosinase activity and potentiated the inhibition of in situ thymidylate synthase by N-Ac-4-S-CAP. The inhibition of in situ thymidylate synthase by both drugs in pigmented melanoma cells correlated with the inhibition of DNA synthesis and cell growth and was not due to an indirect effect caused by inhibition of the enzyme dihydrofolate reductase. 4-S-CAP inhibition of thymidylate synthase activity in cell free extracts required oxidation of the drug. In the presence of tyrosinase, the concentration causing a 50% inhibition of thymidylate synthase activity (IC50) in cell-free extracts was less than 10 microM, but no inhibition was observed in its absence, even at a drug concentration of 500 microM. Two reducing agents, dithioerythritol and glutathione, effectively blocked the inhibition of thymidylate synthase by oxidized 4-S-CAP. In pigmented melanoma cells containing the enzyme tyrosinase, the quinone-mediated mechanism of inhibition of DNA synthesis via inhibition of thymidylate synthase may be uniquely important in the expression of phenolic amine cytotoxicity.
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PMID:Thymidylate synthase as a target enzyme for the melanoma-specific toxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol. 150 78

Cytodifferentiation in many melanocytic cells is regulated through the adenylate cyclase-cAMP pathway. To analyse the molecular changes associated with this process we have compared the proteins produced by two closely related cell lines which, though derived from a single cell line, respond very differently to modulation of this signalling pathway. The human melanoma cell line DX3 shows little change in in vitro characteristics following treatment with cAMP elevating agents; in contrast the more malignant DX3 LT5.1 variant, derived from the DX3 parental line, shows pronounced dendrification, decreased proliferation and a reduction in metastatic capacity after similar treatment. The two cell lines were treated with phosphodiesterase inhibitors for 5 days and then processed for two-dimensional gel characterization using an immobilized pH gradient for the IEF dimension. Proteins were detected by silver staining the gels and protein intensities were digitized using a laser densitometer. Two-dimensional gel patterns were edited, matched and a melanoma protein database of 637 spots constructed using PDQUEST software on an Orion 1/05 computer. Eleven proteins were lost and four new proteins were detected in both cell lines following treatment. Twenty-two proteins were present in DX3 LT5.1 after treatment but not in untreated lines or treated DX3. These differentially expressed proteins may be associated with the observed changes in differentiation patterns and metastasis. Our results illustrate the resolving power of this technique and suggest potential applications to the study of cellular differentiation.
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PMID:Changes in protein expression during melanoma differentiation determined by computer analysis of 2-D gels. 206 Jan 82

The thymidine analog 5-bromodeoxyuridine (BrdU) suppresses pigmentation and tyrosinase activity in Syrian hamster melanoma cells W1-1-1. Studies on the molecular mechanism of suppression of pigmentation indicated that BrdU treatment affects the level of tyrosinase gene transcripts. No detectable tyrosinase message was found by Northern blot analysis in cells cultured in the presence of BrdU at concentrations even as low as 0.2 microM. The level of tyrosinase mRNA was found to reflect the level of pigmentation and tyrosinase activity. Studies with dibutyryl cyclic AMP (cAMP) showed that it inhibited pigment synthesis in W1-1-1 cells. With increasing concentrations of cAMP ranging from 10 microM to 300 microM, pigmentation and tyrosinase activity decreased progressively. This inhibition was found to be associated with a corresponding decrease in the level of tyrosinase mRNA. W1-1-1 cells were found not to respond to melanocyte stimulating hormone (MSH). There was no change in pigmentation, tyrosinase activity, or tyrosinase mRNA level in W1-1-1 cells in the presence of MSH. Similarly, theophylline, a phosphodiesterase inhibitor, had no effect on pigmentation or tyrosinase activity in W1-1-1 cells.
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PMID:Bromodeoxyuridine- and cyclic AMP-mediated regulation of tyrosinase in Syrian hamster melanoma cells. 217 54

The purpose of this investigation was to identify those agents and combinations of agents that help convert murine melanoma cells to cells of differentiated (normal-like) phenotype in culture. The agents used were 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (R020-1724), which is an adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor that has never been tested on melanoma cells in culture, and d-alpha tocopheryl succinate (vitamin E succinate), which has previously been shown to inhibit growth and induce morphological differentiation in melanoma cells. The results indicated that R020-1724 by itself inhibited growth, reduced survival, caused morphological differentiation and increased the melanin content (one of the biochemical differentiated functions) in melanoma cells. Vitamin E succinate had a similar effect on the melanoma cells, which supports past research on this vitamin. A combination of R20-1724 and vitamin E succinate had a significantly greater effect on the melanoma cells than either of the agents by themselves. The agents identified in this study may provide useful tools for studying the mechanisms of differentiation in melanoma cells.
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PMID:Induction of differentiated phenotypes in melanoma cells by a combination of an adenosine 3',5'-cyclic monophosphate stimulating agent and D-alpha tocopheryl succinate. 253 39

1,5-Dihydro-7-(1-piperidinyl)-imidazo[2,1-b]quinazolin-2(3H)-one dihydrochloride hydrate (DN-9693), a new c-AMP: phosphodiesterase inhibitor was examined for its inhibitory effects on platelet aggregation induced by metastasizing tumor cells and on blood-borne metastases of these tumors. 1-3 microM of DN-9693 completely inhibited platelet aggregation induced by B16 melanoma subline BL6 and Lewis lung carcinoma (3LL) cells. Platelets prepared from mice intravenously or orally administered with DN-9693 failed to aggregate after the addition of BL6 cells. Intravenous injection of DN-9693 was effective in protecting the mice inoculated with 1 X 10(6) BL6 cells against acute pulmonary embolic death. Either intravenous or oral administration of DN-9693 (1-10 mg/kg) sufficiently suppressed thrombus formation and subsequent pulmonary metastasis caused by intravenously inoculated BL6 or 3LL cells. Spontaneous pulmonary metastasis of 3LL was also inhibited by DN-9693. Continuous administration of DN-9693 during and after surgical excision of the primary tumors was the most effective treatment against the development of pulmonary metastases of 3LL.
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PMID:Effects of DN-9693, a new metastasis inhibitor, on murine hematogenous metastasis. 301 18

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


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