Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.17 (ornithine decarboxylase)
 6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver ornithine decarboxylase (ODC) activity and content of S-adenosyl-L-methionine (SAM) and its catabolite 5'-methylthioadenosine (5'-MTA) were determined in the late stages of hepatocarcinogenesis. Wistar rats received one diethylnitrosamine dose, followed by a partial hepatectomy at the midpoint of a 15-day treatment with 2-acetylaminofluorene (2-AAF), and then by an 18-week phenobarbital (PB) treatment. Thirty-eight per cent of liver was gamma-glutamyltranspeptidase (GGT)-positive and no visible nodules and hepatocellular carcinomas developed 16 weeks after starting 2-AAF feeding. Hyperplastic nodules and hepatocellular carcinomas were found on weeks 24 and 56 respectively. On weeks 24 and 56 only approximately 10% of liver was occupied by GGT-positive foci. At all times studied the foci exhibited a low labeling index (LI), and liver ODC activity was near control values. By contrast, a high ODC activity and LI and a low SAM and 5'-MTA levels were found in hyperplastic nodules and neoplasia. These tissues exhibited a high 5'-MTA phosphorylase activity. SAM administration during PB treatment, caused a 25-36% fall of GGT-positive liver and prevented the development of hyperplastic nodules and hepatocellular carcinomas. This was coupled to a sharp increase of SAM and 5'-MTA liver contents. SAM and 5'-MTA inhibited hepatocyte DNA synthesis in vitro. The addition of 5'-MTA to the reaction mixture for the ODC assay strongly inhibited ODC activity. However, the preincubation of SAM with liver homogenates or hepatocytes, used to prepare crude ODC, was necessary to inhibit ODC activity by SAM. Adenine, an inhibitor of 5'-MTA-phosphorylase, enhanced inhibition of DNA synthesis and ODC activity by SAM and 5'-MTA. Thus, during a prolonged promoting treatment a selected population of GGT-positive foci appears to acquire a stable phenotype characterized by a high DNA and polyamine synthesis. The development of nodules and carcinomas is associated with low SAM and 5'-MTA contents and high ODC activity and LI. 5'-MTA accumulation, during SAM administration, is probably responsible for the inhibition of promotion by SAM.
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PMID:Variations of ornithine decarboxylase activity and S-adenosyl-L-methionine and 5'-methylthioadenosine contents during the development of diethylnitrosamine-induced liver hyperplastic nodules and hepatocellular carcinoma. 288 49

The antiproliferative effects of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) are limited by the inability of the compound to deplete completely cellular polyamine pools. 5'-Deoxy-5'-methylthioadenosine (MeSAdo), the purine end product of the polyamine biosynthetic pathway, is an inhibitor of spermine and spermidine synthesis. Furthermore, a substantial number of human tumors are deficient in MeSAdo phosphorylase, and cannot degrade MeSAdo. It therefore seemed possible that DFMO and MeSAdo could interact synergistically to inhibit polyamine synthesis in MeSAdo phosphorylase-deficient malignant cells. To test this hypothesis, we have analyzed the effects of DFMO, in combination with MeSAdo, on polyamine synthesis and growth in a MeSAdo phosphorylase-deficient murine lymphoma cell line (R1.1-H), and a MeSAdo resistant mutant (R1.1-H3). Cultivation of the R1.1-H3 cells in medium containing 250 microM DFMO and 500 microM MeSAdo caused profound depletion of putrescine, spermidine, and spermine, and the accumulation of both decarboxylated S-adenosylmethionine and its acetylated derivative to levels that exceeded by nearly 3-fold the total cellular content of S-adenosylmethionine. Similarly, DFMO sensitized the lymphoma cells to the growth inhibitory effects of MeSAdo. Supplementation of the medium with putrescine, spermidine, or spermine partially protected R1.1-H3 cells from the DFMO-MeSAdo drug combination. It is conceivable that MeSAdo, or related nucleosides, may potentiate the cytostatic effects of DFMO toward MeSAdo phosphorylase-deficient tumors.
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PMID:Synergistic inhibition of polyamine synthesis and growth by difluoromethylornithine plus methylthioadenosine in methylthioadenosine phosphorylase-deficient murine lymphoma cells. 310 48

The control of polyamine synthesis in neoplastic cells is complex and incompletely understood. Using murine lymphoma cells deficient in methylthioadenosine (MTA) phosphorylase, we have analyzed the role of MTA in the regulation of ornithine decarboxylase and S-adenosylmethionine (SAM) decarboxylase, the two rate-limiting enzymes in the polyamine-biosynthetic pathway. The addition of MTA to the enzyme-deficient lymphoblasts induced within 1 to 3 h an increase in the activities of both decarboxylases and an accompanying rise in putrescine and decarboxylated SAM levels. The ornithine decarboxylase inhibitor alpha-difluoromethylornithine blocked the MTA-triggered accumulation of putrescine but not decarboxylated SAM. In a reciprocal manner, the SAM decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) prevented the accretion of decarboxylated SAM but not putrescine. The MTA-induced rise in SAM decarboxylase and ornithine decarboxylase activities preceded by several hours changes in spermidine or spermine pools. However, MTA decreased the flux through the polyamine-synthetic pathway, as estimated by the incorporation of radioactive ornithine into spermine. Similar changes in polyamine metabolism were observed in a secondary mutant deficient in MTA phosphorylase, but resistant to MTA toxicity. These results suggest that the velocity of polyamine synthesis, or the concentration of MTA itself, may regulate ornithine decarboxylase and SAM decarboxylase activities through separate, growth-independent mechanisms.
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PMID:Independent regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase in methylthioadenosine phosphorylase-deficient malignant murine lymphoblasts. 392 3