Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Continuous exposure for 96 hr of B16 melanoma cells in culture to 2.5 mM alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, resulted in a marked increase in the activity of the enzyme tyrosinase, and also 20% cell kill as assessed by clonogenic assay. A 4-hr exposure to 0.4 mM 3,4-dihydroxybenzylamine (DHBA), a compound which is melanolytic due to its conversion to a cytotoxic quinone by the tumor specific enzyme tyrosinase, was found to be approximately equitoxic to 2.5 mM DMFO. However, a combination of DFMO (2.5 mM) and DHBA (0.4 mM) produced greater than 95% cell kill. This observed cytotoxicity with the combination suggests that induction of tyrosinase by DFMO sensitizes B16 melanoma cells to the melanolytic activity of DHBA. Oral administration of DFMO to mice bearing subcutaneous B16 melanomas also resulted in marked increases in the activity of tyrosinase in the tumor tissue. In mice inoculated intraperitoneally with 10(5) B16 melanoma cells, administration of DFMO via the drinking water (2%) increased the survival time by 8.5 days, whereas intraperitoneal administration of 300 mg/kg of DHBA for 14 days resulted in an increase in life span of 4.5 days compared to untreated controls. A combination of DFMO and DHBA prolonged the survival time by 14.6 days. These results indicate that DFMO in combination with an appropriate tyrosinase-dependent melanolytic agent might be useful in the chemotherapy of malignant melanomas.
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PMID:Potentiation by alpha-difluoromethylornithine of the activity of 3,4-dihydroxybenzylamine, a tyrosinase-dependent melanolytic agent, against B16 melanoma. 392 51

The objective of the present study was to investigate the effect of polyamine depletion by alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, on the growth and differentiation of B16 melanoma cells grown in culture and also as solid tumors in mice. Polyamine depletion by DFMO (2.5 mM) resulted in a complete inhibition of cell growth in culture and a 90% inhibition of viability of melanoma cells as determined by clonogenic assay at the end of 7 days after DFMO treatment. These results indicate that polyamine depletion induced by DFMO is cytotoxic to B16 melanoma cells in culture. Furthermore a 2- to 5-fold increase in tyrosinase activity and 10-fold accumulation of melanine were observed in polyamine depleted cells compared to control cultures. These effects of DFMO could easily be reversed by the addition of putrescine simultaneously with DFMO. Administration of different doses of DFMO in drinking water to B16 melanoma tumor bearing mice also resulted in an increase in tyrosinase activity and a dose dependent inhibition (86-90%) of tumor growth. Although one cannot rule out the possibility of induction of differentiated phenotype as a result of antiproliferative activity of DFMO, the data presented indicate that the unique sensitivity of melanoma to DFMO may be due to a combination of cell growth inhibition and concomitant induction of differentiation upon polyamine depletion. The results of the present study indicate that polyamines play an important role in growth and differentiation of melanoma and also provide an example of inhibition of tumor cell growth by induction of cellular differentiation.
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PMID:Effect of inhibition of polyamine biosynthesis by DL-alpha-difluoromethylornithine on the growth and melanogenesis of B16 melanoma in vitro and in vivo. 392 49

Transglutaminase (TGase; R-glutaminyl-peptide:amine gamma-glutamyltransferase, EC 2.3.2.13) and ornithine decarboxylase (ODCase; L-ornithine carboxy-lyase, EC 4.1.1.17) activities were measured after the addition of retinoid analogs to Chinese hamster ovary (CHO) cells released from quiescence and Cloudman S91 (CCL 53.1) mouse melanoma cells stimulated to differentiate with alpha-melanocyte-stimulating hormone (MSH, melanotropin). In both cell culture lines, we detected a biphasic increase in TGase activity and a single peak of ODCase activity within 7 hr after release or stimulation. Retinoid analogs altered the expression of the initial TGase peak in both CHO and melanoma cells. Retinol increased the activity of TGase 1 hr after release in CHO cells, and the activity remained elevated until hr 4. A broad peak of TGase activity also occurred after the addition of alpha-difluoromethylornithine, an irreversible inhibitor of ODCase, and after addition of alpha-difluoromethylornithine plus retinol. In mouse melanoma cells, retinoic acid plus MSH markedly enhanced the activity of the initial TGase peak compared to MSH alone. Retinoic acid alone also increased TGase activity biphasically in these cells without the addition of MSH. These studies suggest that retinoid effects that increase TGase activity may alter the ODCase expression in proliferation and differentiation.
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PMID:Retinoids increase transglutaminase activity and inhibit ornithine decarboxylase activity in Chinese hamster ovary cells and in melanoma cells stimulated to differentiate. 612 41

Effects of 1,15-bis(ethylamino)-4,8,12-triazapentadecane (BE3333), the least toxic bis(ethyl)pentaamine, on the growth of tumor cells were studied in in vitro systems and with tumor xenografts in mice. BE3333 suppressed ornithine decarboxylase and S-adenosylmethionine decarboxylase, induced spermidine/spermine N1-acetyltransferase, and thus decreased the amount of polyamines. BE3333 accumulated in cells at a concentration 3-5-fold that of spermine in control cells through the polyamine transport system. The accumulated BE3333 inhibited protein synthesis, especially mitochondrial protein synthesis, and decreased the amount of ATP. The inhibition of protein synthesis was correlated with the subsequent inhibition of cell growth. BE3333 showed inhibitory effects in in vitro systems against the growth of mouse FM3A mammary carcinoma cells, human SW480 and SW620 colon tumor cells, Lu-65A and A549 lung tumor cells, MCF-7 breast tumor cells, and MALME-3M and A375 melanoma cells at a range of 0.5-10 microM. Intravenous (30 mg/kg) or i.p. (50 mg/kg) daily injections of BE3333 for 5 or 7 days greatly suppressed the growth of human colon tumor SW620 xenotransplanted into nude mice. Similar antitumor activity was obtained with continuous infusion of BE3333 into the peritoneal cavity (80 mg/kg), but not with p.o. administration (200 mg/kg). BE3333 also showed inhibitory effects against the growth of lung tumors (Lu-65, Lx-1, Lc-1, and Lu-61), stomach tumors (Sc-6 and St-15), and melanoma (SEKI) xenotransplanted into nude mice. The results indicate that BE3333 is effective against both rapid- and slow-growing tumors, with reasonable short-term host toxicity.
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PMID:Inhibition of the growth of various human and mouse tumor cells by 1,15-bis(ethylamino)-4,8,12-triazapentadecane. 778 Sep 77

Certain N-alkylated analogues of the natural polyamine spermine, such as N1,N11-diethylnorspermine (DENSPM), rapidly deplete intracellular polyamine pools by down-regulating the biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, and by potently up-regulating the polyamine catabolizing enzyme, spermidine/spermine N1-acetyltransferase. On the basis of previously reported antitumor activity in human tumor xenograft model systems, DENSPM is currently undergoing Phase I clinical trials against human melanoma and other solid tumors. The antiproliferative activity of this analogue against the multidrug resistance (MDR) phenotype was examined in three MDR sublines of human melanoma RPMI-7932 cells, which were shown to be 2-to 10-fold resistant to classical MDR agents. These MDR lines had been separately derived using different selecting agents (Lemontt et al., Cancer Res., 48: 6344-6353, 1988). Subline functional resistance due to P-glycoprotein was confirmed by decreased retention of rhodamine 123 relative to parent cells as detected by flow cytometry. Although the three sublines were 2- to 10-fold less sensitive than the parent line to classical MDR-type agents, they were found in dose-response studies to be significantly more sensitive to DENSPM than the parent line. In addition, they showed a distinct cytotoxic response after a 48-h treatment with 10 microM DENSPM, which was not apparent in the parent line. Growth sensitivity of the sublines to the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, or the S-adenosylmethionine decarboxylase inhibitor, CGP-48664, was found to be similar to parent cells. The ratio of the key biosynthetic enzyme activities for ornithine decarboxylase and S-adenosylmethionine decarboxylase was found to be 3.5- to 5-fold higher in all three sublines, due mainly to increases in the former enzyme. This imbalance produced unusually high putrescine pools. Although DENSPM down-regulation of decarboxylase activities and potent up-regulation of spermidine/spermine N1-acetyltransferase activity occurred similarly in both parent and variant lines, polyamine depletion was greater in the variant lines. Collateral sensitivity of the MDR sublines to DENSPM is partially attributable to the finding that analogue (and spermidine) uptake in the sublines was about 2-fold higher (after 2 h) than in the parent cells. The presence of disturbances in polyamine homeostasis and increased sensitivity to DENSPM in three independently selected cell line variants suggests that they may be generally associated with the MDR phenotype in human melanoma and possibly other tumor cells. The collateral sensitivity of human melanoma MDR variants to DENSPM represents a possible therapeutic indication which should be considered during the ongoing clinical evaluation of this drug.
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PMID:Collateral sensitivity of human melanoma multidrug-resistant variants to the polyamine analogue, N1,N11-diethylnorspermine. 795 23

Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.
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PMID:CGP 48664, a new S-adenosylmethionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity. 820 41

In in vitro systems, the spermine analogue, N1,N11-bis(ethyl)norspermine (BENSPM), suppresses the polyamine biosynthetic enzymes, ornithine and S-adenosylmethionine decarboxylase (ornithine decarboxylase and S-adenosylmethionine decarboxylase, respectively), greatly induces the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), depletes polyamine pools, and inhibits cell growth. Against MALME-3 M human melanoma xenografts, BENSPM and related homologues demonstrate potent antitumor activity that has been found to correlate positively with their ability to induce SSAT activity in vitro. Herein, we further evaluate the antitumor activity of BENSPM and at the same time characterize the biochemical effects of BENSPM treatment on polyamine metabolism of selected normal and tumor tissues. At 40 mg/kg 3 times/day for 6 days i.p., BENSPM suppressed growth of MALME-3 M human melanoma xenografts during treatment and for 65 days afterwards. Similar antitumor activity was obtained with 120 mg/kg once daily for 6 days and 40 mg/kg once daily for 6 days, indicating that against this tumor model, the dosing schedule can be relaxed up to sixfold without compromising antitumor activity. When MALME-3 M tumor-bearing mice were retreated with BENSPM 2 weeks after the first treatment at 40 mg/kg 3 times/day for 6 days, initial tumor volumes of 85 mm3 were reduced to < 10 mm3. Analysis of melanoma, liver, and kidney tissues from mice treated with 40 mg/kg 3 times/day for 6 days revealed relatively similar accumulations of BENSPM in all tissues at levels greater than the original total content of polyamine pools. By 2 weeks following treatment, BENSPM pools in normal tissues were almost gone, whereas in tumor tissues significant amounts (40%) were still retained. The biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, gave no indication of enzyme suppression (or increase) by the analogue as typically occurs in vitro. By contrast, SSAT was induced from an average of < 50 pmol/min/mg in control tissues to 320 pmol/min/mg in liver, 1255 pmol/min/mg in kidney, and 13,710 pmol/min/mg in MALME-3M tumor. Two weeks later, SSAT activity was still 12 times higher in tumor than in kidney. Polyamine pools (putrescine, spermidine, and spermine) were reduced after treatment in all tissues and approached near-total depletion in the tumor. Good antitumor activity and even more potent induction of SSAT (i.e., 26,680 pmol/min/mg) was also observed in PANUT-3 human melanoma xenografts. Overall, the findings reveal meaningful antitumor activity by BENSPM against 2 human melanoma xenografts and provide in vivo evidence consistent with SSAT-induced polyamine depletion playing a determining role in at least the initial phase of the antitumor response.
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PMID:Antitumor activity of N1,N11-bis(ethyl)norspermine against human melanoma xenografts and possible biochemical correlates of drug action. 842 91

Experimental studies have demonstrated that carcinogenesis is a multistep process in which inappropriate proliferation of cells is a critical determinant. Polyamines support sustained growth and are highly regulated in all cells. The rate limiting enzyme for this pathway is ornithine decarboxylase (ODC), an enzyme that exhibits rapid turnover, and converts the amino acid ornithine to putrescine, which in turn is converted to the longer chain amines spermidine and spermine. In animal models of colon carcinogenesis, inhibition of ODC by difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor, reduces the number and size of colon adenomas and carcinomas. DFMO was first ineffective when used clinically to treat acute leukemia or melanoma and caused clinically significant but reversible ototoxicity. Subsequently, we performed a series of analyses demonstrating that hearing loss was rare below a total cumulative dose of 150 gm/m2 and increased with total cumulative dose of DFMO. The hearing loss was reversible with rapid reversion to baseline hearing. We and others have conducted Phase IIa trials to determine the lowest dose at which DFMO can decrease colon mucosa polyamine content, and found that an oral dose as low as 0.25 gm/m2 per day (perhaps lower) decreases colon tissue putrescine content and lowers the spermidine/spermine ratio. We are currently conducting a long-term randomized Phase IIb trial which serially measures the long-term effect of several low doses (and placebo) of DFMO on sustaining polyamine depletion in colon mucosa, as well as carefully monitoring hearing by audiometry and other sophisticated tests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer. 853 89

A human type I IL-1 receptor expression plasmid has been constructed and used to transfect human melanoma cells (A375-5), which have been shown to be unresponsive to the antiproliferative effect of IL-1. Five stable transfectant cell lines have been established, of which three are sensitive and the other two resistant to the anti-proliferative effect of IL-1. All the transfectant cell lines, but not progenitor A375-5 cells, expressed functional type I IL-1 receptors and could produce IL-6 in response to IL-1, suggesting that the unresponsiveness of A375-5 melanoma cells is exactly due to an IL-1 receptor deficiency. The three IL-1-sensitive stable transfectant cell lines expressed much more type I IL-1 receptor than the IL-1-sensitive A375-6 cells, thus they are expected to be useful for investigating the signal transduction pathway of IL-1-induced growth inhibition in melanoma cells. The two resistant cell lines produced comparable amounts of IL-6 in response to IL-1, as sensitive cell lines did, indicating that IL-6 induction does not play a major role in IL-1-induced growth inhibition in these melanoma cells. The possibility of an IL-6 receptor and/or IL-6 receptor signaling deficiency was ruled out as the IL-1-sensitive and -resistant transfectants responded similarly to a high dose of exogenous human recombinant IL-6. Examination of the ornithine decarboxylase (ODC) activity of recombinant human IL-1 alpha treated cells showed that all the sensitive but none of the resistant cell lines could down-regulate their ODC activity. These results suggest that IL-1-induced ODC activity down-regulation is an important step in the signal transduction pathway of IL-1-induced growth inhibition of melanoma cells.
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PMID:Transfection of human melanoma cells with type I interleukin-1 (IL-1) receptor cDNA rendered them IL-1-responsive and revealed the importance of ODC activity down-regulation in IL-1-induced growth inhibition. 857 96

Ornithine decarboxylase (ODC) and spermidine/ spermine N1-acetyltransferase (SSAT) are short-lived polyamine enzymes with rate-limiting roles in controlling polyamine biosynthesis and catabolism, respectively. We have found that treatment of MALME-3M human melanoma cells for 6 h with 10 micrograms/ml cycloheximide (CHX) increases ODC and SSAT mRNA 6-9-fold. When cells containing CHX-induced SSAT mRNA were washed and post-incubated for an additional 6 h in drug free media, enzyme activity increased only 2-fold above that in untreated cells despite the > 6-fold increase in accumulated mRNA. Inclusion of 10 microM spermine or spermidine in the post-incubation medium increased SSAT activity approximately 7-fold without further elevating SSAT mRNA levels. This indicates post-transcriptional regulation which, due to the similarity between polyamine-mediated increases in SSAT activity and available mRNA, probably occurs at the level of mRNA translation. In contrast to the SSAT response, polyamines markedly reduced ODC activity (but not mRNA) to one sixth that in cells not exposed to polyamines. The findings illustrate how via post-transcriptional mechanisms, shifts in intracellular polyamine pools can simultaneously and differentially regulate polyamine biosynthesis and catabolism. It is hypothesized that these post-transcriptional responses enable cells to rapidly and sensitively control intracellular spermidine and spermine pools.
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PMID:Differential post-transcriptional control of ornithine decarboxylase and spermidine-spermine N1-acetyltransferase by polyamines. 870 37


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