Detail of "52128-35-5"

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A methotrexate-resistant human breast cancer cell line with multiple defects, including diminished formation of methotrexate polyglutamates

A methotrexate-resistant human breast cancer cell line with multiple defects, including diminished formation of methotrexate polyglutamates. Cowan, Kenneth H.; Jolivet, Jacques (Div. Cancer Treat., Natl. Cancer Inst., Bethesda, MD 20205, USA). J. Biol. Chem., 259(17), 10793-800 (English) 1984. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Methotrexate (MTX) [59-05-2]-resistant human breast cancer cells (MTXR ZR-75) were obtained following serial passage of the wild-type ZR-75-1 cells (wild-type ZR-75) in MTX. The resistant cell line contains neither quant. nor qual. changes in dihydrofolate reductase compared to the parental line. Resistance is assocd. with a 3-fold decrease in MTX transport into MTXR ZR-75 cells as well as a 3-fold decrease in the activity of thymidylate synthetase [9031-61-2] in the resistant subline. Moreover, marked differences were obsd. between the wild-type and MTXR ZR-75 cells in their ability to convert MTX to its polyglutamate derivs. Wild-type ZR-75 cells accumulate significant intracellular levels of antifolates during prolonged (24 h) exposure to 2 mM MTX, due to the formation of MTX polyglutamate [82334-40-5]. In contrast, essentially no polyglutamates are formed in the MTXR cells even during conditions which result in a vast excess of free intracellular drug in these cells. This defect is not assocd. with any apparent change in the activity of the enzyme folylpolyglutamyl synthetase [63363-84-8], nor is there any alteration in the apparent Km of this enzyme for MTX in the resistant cells. Further studies demonstrate that the MTXR ZR-75 cells are cross-resistant to antifolate analogs which can be converted to polyglutamate derivs. (aminopterin [54-62-6] and dichloromethotrexate [528-74-5]), yet they are relatively sensitive to antifolate analogs such as 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine [7761-45-7], triazinate) [41191-04-2], and trimetrexate [52128-35-5], which cannot be converted to polyglutamate forms. A new mechanism (diminished accumulation of MTX polyglutamates) assocd. with resistance to MTX is identified, which leads addnl. support to the hypothesis that the formation of these derivs. is an important determinant of MTX cytotoxicity.

Influence of hypoxia on the metabolism and biliary excretion of trimetrexate by the isolated perfused rat liver

Influence of hypoxia on the metabolism and biliary excretion of trimetrexate by the isolated perfused rat liver. Webster, Lorraine K.; McCormack, John J. (Vermont Reg. Cancer Cent., Univ. Vermont, Burlington, VT 05405, USA). Biochem. Pharmacol., 35(24), 4587-9 (English) 1986. CODEN: BCPCA6. ISSN: 0006-2952. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) In the isolated perfused rat liver, the elimination of trimetrexate [52128-35-5], and the prodn. and elimination of 2 metabolites, was inhibited by hypoxia. Bile flow and biliary excretion of the metabolites were diminished by hypoxia. It is also evident that, for oxidatively produced metabolites which are primarily excreted in the bile, a return to normal oxygenation after a hypoxic episode can lead to sharp increases in their concns. in the perfusate.