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Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.
Leukemia
February 2002
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)).
View Article and Find Full Text PDF6-Mercaptopurine: cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts.
Biochem Pharmacol
April 1993
Department of Pediatrics, St. Radboud University Hospital of Nijmegen, The Netherlands.
The effects of prolonged exposure to 2 and 10 microM 6-mercaptopurine (6MP) in the human lymphoblastic T-cell line MOLT-4 were studied with respect to cell-kinetic parameters, phosphoribosyl pyrophosphate (PRPP) and purine ribonucleotide levels, formation of 6MP-nucleotides, especially methyl-thio-IMP (Me-tIMP), DNA and RNA synthesis ([32P] incorporation), and [8-14C]6MP incorporation into newly synthesized DNA and RNA. The results provided new insights into the complex mechanism of action of 6MP in human malignant lymphoblasts. Exposure to 2 microM 6MP resulted in a rapid inhibition of purine de novo synthesis (PDNS) by increased levels of Me-tIMP, resulting in increased PRPP levels and decreased purine ribonucleotides, affecting cell growth and clonal growth, and less cell death.
View Article and Find Full Text PDFThe activation of purine antimetabolites to their respective nucleotides is a step critical to their effectiveness as chemotherapeutic agents. Erythrocytes, with their relatively simple purine metabolism, are useful as a model for identifying mechanisms which enhance this 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP)-dependent activation. We previously showed that pyrroline-5-carboxylate, a physiologic intermediate in the interconversions of proline, ornithine, and glutamate, markedly stimulated the pentose phosphate pathway, increased the formation of P-Rib-PP, and increased purine incorporation into nucleotides.
View Article and Find Full Text PDF[Butoctamide enhancement of the antitumor activity of 6-mercaptopurine on Ehrlich solid tumors in mice (author's transl)].
Nihon Yakurigaku Zasshi
February 1981
Effects of butoctamide (N-(2-ethylhexyl)-3-hydroxybutyramide, L-2) on the antitumor activity of 6-mercaptopurine (6-MP) against Ehrlich solid tumors in mice were investigated. No change was observed in tumor growth after either oral or intraperitoneal administration of butoctamide (100 mg/kg/day X 7). This drug increased the activity of a low dose of 6-MP (2.
View Article and Find Full Text PDFThe mechanism of inhibition of DNA synthesis by 1-beta-D-arabinofuranosyl-ATP (ara-ATP) and the potentiation of this inhibition by 6-mercaptopurine ribonucleoside 5'-monophosphate (6-MPR-P) have been investigated with mammalian DNA polymerase delty by using poly(dA-dT) as the template. The inhibition of DNA synthesis by ara-ATP correlates with incorporation of ara-AMP into poly(dA-dT). Nearest-neighbor analysis indicates that ara-AMP does not act as an absolute chain terminator but rather that chains with 3'-terminal arabinosyl nucleotides are extended slowly.
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