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)

The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1 beta produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1 beta (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of anti-inflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclooxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4Cl), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenzamide) were inactive. In contrast, corticosteroids (dexamethasone, hydrocortisone, and paramethasone acetate), tilorone, and protein kinase C inhibitors (1-[5-isoquinolinyl-sulfonyl]-2-methylpiperazine and staurosporine) significantly inhibited IL-1 beta-mediated A375.6 cytolysis. These compounds also interfered with tumor necrosis factor-mediated lysis of A375.6, suggesting common mechanisms of tumor cytotoxicity by these monokines. This model may be useful for delineating intracellular biochemical events integral to IL-1 action.
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PMID:Potent inhibition of interleukin 1 beta-mediated human melanoma (A375.6) lysis by corticosteroids, staurosporine, and tilorone. 262 25

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
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PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27

Human 253J urinary carcinoma cells and the F1 (low-metastatic) and F10 (high-metastatic) variants of the B16 murine melanoma cell line have been shown to activate heparinized human platelets by an adenosine diphosphate (ADP)-dependent mechanism based on inhibition by creatine phosphate/creatine phosphokinase and the identification of aggregating concentrations (1 to 2 mumol/L) of ADP in cell-free culture supernatants by high-performance liquid chromatography. Aggregation did not occur in citrated samples, and hirudin was without effect. Studies were carried out to determine whether extracellular ADP arose from nonspecific cell damage during cell isolation and manipulation or was a specific process under control of the tumor cells themselves. Tumor cell damage during harvesting was shown not to be a factor because the amounts of ADP produced by the three cell lines (a) were inversely related to the appearance of lactic dehydrogenase in the culture supernatants and (b) were similar when measured in confluent monolayers, either in tumor cells after detachment and resuspension or after crossover studies involving culture in, alternatively, Hanks' balanced salt solution and minimal essential medium. Metabolic control of ADP production was indicated by the fact that (a) it was not dependent on cell number, which suggests feedback inhibition; (b) it was reduced 60% when tumor cells were treated with p-chloromercuribenzene sulfonate; and (c) it was completely abolished in those treated with iodoacetic acid, which might be expected to increase nonspecific leakage. These studies indicate that ADP production by these three lines does not arise due to leakage induced by nonspecific membrane damage during cell harvesting and manipulation but is a discrete process under metabolic control of the tumor cells. Moreover, in B16 murine melanoma cells the ability to produce ADP and to support platelet aggregation appears to be unrelated to metastatic potential insofar as identical results were obtained with the F1 and F10 variants.
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PMID:Platelets in tumor metastasis: generation of adenosine diphosphate by tumor cells is specific but unrelated to metastatic potential. 283 29

Specific markers (growth, melanogenesis) of B16 murine melanoma cells in culture were used as indicators of toxin production by Aeromonas hydrophila. Cytotonic enterotoxinlike activity (inhibited growth, raised tyrosinase activity, and melanin accumulation) occurred at cytotoxic end points of purified beta-hemolysin and several culture filtrates. Antihemolysin rabbit serum inhibited this activity. A hemolysin-neutralized culture filtrate concentrate (10X) failed to elevate tyrosinase relative to untreated and cholera toxin treated controls. Similar dilution profiles using Chinese hamster ovary cells showed limited cell extension only at cytotoxic end points with antihemolysin inhibiting this activity. Cytotoxicity of Chinese hamster ovary cells and B16 cells was proportional to hemolytic activity, with B16 cells showing about 100-fold greater sensitivity on a per cell basis. Cell culture cytotoxicity attributed to beta-hemolysin correlated with reactivity in rabbit ileal loop assays. The ADP-ribosyl transferase activity of concentrated (10X) A. hydrophila culture filtrates and fractions thereof was negative. Apparently sublethal doses of A. hydrophila beta-hemolysin can nonspecifically stimulate cyclic adenosine monophosphate mediated events in melanoma and Chinese hamster ovary cell assays, producing lower activities than cholera toxin with shorter lag times.
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PMID:Melanogenesis in murine B16 cells exposed to Aeromonas hydrophila cytotoxic enterotoxin. 309 98

Possible prophylactic antitumor and/or antimetastatic effects of long-term oral administration of a potent inhibitor of platelet aggregation, the pyrimido-pyrimidine derivative RA233, were assessed using four phenotypically distinct clones of the mouse B16 melanoma. The clones tested included: a poorly tumorigenic, very slowly growing and poorly metastatic population (G3.15); a moderately tumorigenic and slowly growing population that frequently metastasizes to the lungs (G3.5); a highly tumorigenic, moderately growing and highly metastatic population (G3.12); and a highly tumorigenic and rapidly growing population that is generally nonmetastatic but can be slightly metastatic when tumors are initiated by very small numbers of cells (G3.26). Addition of 0.5 mg/ml RA233 to the drinking water continuously from the time of subcutaneous injection of cultured tumor cells until death from tumor growth, which resulted in a daily uptake of 80-100 mg/kg of drug per mouse, failed to significantly influence the tumorigenicities, tumor growth rates, metastatic incidences, or metastatic burdens of any of these clones. RA233 at doses equivalent to those delivered daily to experimental animals strongly inhibited ADP-induced aggregation of homologous C57BL/6 mouse platelets and exhibited selective anti-proliferative effects on cultured cells. Although RA233 prolonged bleeding times, pharmacokinetic analysis indicated that clearance of RA233 from mice was so rapid that achievement of sustained circulating levels sufficient to influence tumor cells or platelet-tumor cell interactions by oral administration was unlikely.
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PMID:Failure of orally administered RA233 to influence B16 melanoma growth or metastasis. 359 74

Blood platelets have been suggested to play an important role in modulating the development of experimental metastases. Tumour cells can induce platelet aggregation in vitro and a number of mechanisms have been proposed to explain the in vivo and in vitro observations. In the present study, we used tumour cells cloned from B16 melanoma and mouse mammary tumour virus (MMTV) carcinoma polyclonal populations to check whether tumour cells with low- and high-metastatic behaviour in vivo had different quantitative and qualitative platelet-aggregating activity in vitro. We found no significant quantitative difference between platelet aggregation induced by the low- and the high-metastatic clones. Indeed both the high and the low metastatic B16 melanoma clones poorly aggregated platelets, while both the high and low metastatic MMTV carcinoma clones efficiently aggregated platelets. Both the B16 melanoma and the MMTV carcinoma parental cell lines, which can be classed as intermediate metastatic, aggregated platelets well. However, based on the results with heparin and creatine phosphate/creatine phosphokinase, it appeared that qualitative differences might exist in the mechanism of platelet aggregation by tumour cells. For the parental lines and highly metastatic clone C1 a thrombin-linked component was more important than an ADP-like component, which was nevertheless present, to promote platelet aggregation. For the low-metastatic clone C2, the ADP-like component appeared to be the most important.
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PMID:Tumour-cell-induced platelet aggregation: studies with cloned metastatic and non-metastatic variants. 367 44

The activities of glycogen synthase and phosphorylase were measured and compared to the growth-related variations of glycogen accumulation in three cultured human tumor cell lines: HT-29 (colon carcinoma); MeWo (malignant melanoma); and RT-4 (carcinoma of the urinary bladder). A similar pattern of variations in the enzyme activities was found in the three cell lines. The activities of the a + b forms of glycogen phosphorylase increased throughout the culture period. Maximal activity of phosphorylase a coincided with low intracellular concentrations of glycogen during the period of exponential growth. When the rate of cell division decreased, phosphorylase a activity also decreased while the glycogen levels increased. Glycogen synthase was almost entirely in b form during the entire culture period, i.e., in both the exponential and the stationary phases. In vitro incubation of the cellular extracts without NaF showed, however, that the enzyme could be partially converted to the a form by the endogenous phosphatases. The A0.5 values of the enzyme for glucose-6-phosphate (Glc-6-P) were of the same order of magnitude as the intracellular Glc-6-P concentrations which ranged from 2.2 to 5.4 mM (almost 10 times those reported in normal cells). Similar Glc-6-P values were obtained by two different extraction methods controlled by the intracellular ATP and ADP concentrations. The Km values for uridine-5'-diphosphoglucose were always 2 to 3 times lower than the intracellular uridine-5'-diphosphoglucose concentrations. These results suggest that: (a) in these tumor cells, glycogen is essentially synthesized by glycogen synthase b via an allosteric activation by intracellular Glc-6-P; (b) there is no obvious growth-related control of glycogen synthase activity; and (c) the activity of glycogen phosphorylase seems to be growth dependent with maximal phosphorylase a activities associated with the period of high division rate.
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PMID:Growth-related enzymatic control of glycogen metabolism in cultured human tumor cells. 641 76

The anti-tumour methylating agent 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC) increased the thymidine and deoxycytidine pools but not the deoxyguanosine pool in human melanoma cells. Incorporation of deoxyguanosine and deoxyadenosine was strongly inhibited by MTIC due to formation of the decomposition product 5-aminoimidazole-4-carboxamide (AIC). Theophylline, natural nucleosides and sulphydryl compounds did not affect the toxicity of MTIC in either MTIC-sensitive (Mer-) or autologous-resistant (Mer+) melanoma cells. 3-Aminobenzamide (3 mM for 48 h), an inhibitor of ADP-ribosyl transferase, greatly enhanced MTIC toxicity in the resistant compared with the sensitive cell line.
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PMID:Epigenetic effects of the methylating agent 5-(3-methyl-1-triazeno) imidazole-4-carboxamide in human melanoma cells. 653 46

Prostaglandin D2 spontaneously decomposes at physiological pH and temperature to 9-deoxy-delta 9-PGD2 (designated PGJ2). We developed a TLC procedure for the isolation of PGJ2 which was identified by both proton-NMR and mass spectrometry. Freshly prepared PGJ2 was active in inhibiting aggregation induced by ADP in citrated human platelet rich plasma. As reported by Fukushima et al. (1). PGJ2 was less active (x 0.1-0.25) than PGD2 as an inhibitor. Concentrations of PGJ2 that markedly inhibited aggregation of human platelets were generally incapable of inhibiting aggregation of rat or guinea pig platelets. Using a heterologous system of human platelets mixed with guinea pig plasma samples (2), it was shown that the ability of PGJ2 to inhibit platelet aggregation was lost immediately following intravenous injection in anesthetized guinea pigs. This apparent rapid uptake and/or degradation of PGJ2 might also explain why PGJ2 had no effect on blood pressure of anesthetized guinea pigs. PGJ2 was potent in inhibiting proliferation of cultured vascular smooth muscle cells, mouse melanoma cells and mouse fibroblasts. Less potent anti-proliferative effects were seen with two other degradation products of PGD2, one of which was the delta 12 metabolite reported (3,4) to be formed from PGJ2 in a reaction catalyzed by serum albumin.
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PMID:On the identification and biological properties of prostaglandin J2. 659 46

The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on artificial and spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggregation; namely, 100 mg/kg for ticlopidine, 2 mg/kg for diltiazem, 180 mg/kg for trapidil and 60 mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice. For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutaneously into the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested. Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet-derived growth factor in the growth of metastatic foci.
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PMID:Effects of antiplatelet agents on pulmonary metastases. 672 29


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