DIFFERENTIAL SYNTHESIS OF METHOTREXATE POLYGLUTAMATES IN NORMAL PROLIFERATIVE AND NEOPLASTIC MOUSE-TISSUES INVIVO

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (11) , 4441-4446
Abstract
Synthesis of poly-.gamma.-glutamyl metabolites of methotrexate was demonstrated in mouse small intestine, liver and bone marrow and in L1210 leukemia, sarcoma 180 and Ehrlich tumor cells after s.c. injections of [3H]methotrexate to tumor-bearing mice. Ion-exchange chromatography of tissue extracts resolved 6 peaks of radioactivity believed to represent methotrexate and metabolites with up to 5 additional glutamyl residues. Polyglutamate formation in L1210 cells and small intestine was independent of dose at least to 400 mg/kg as long as intracellular levels of the drug in excess of the dihydrofolate reductase-binding capacity (exchangeable) were maintained. The total amount of polyglutamates and the average length of the polyglutamyl chain increased with time as long as an exchangeable level of the drug was present intracellularly. The extent of metabolism of methotrexate polyglutamates differed among the tissues examined. Although these differences were at times very large, there was no consistent correlation between these differences and other pharmacological parameters of cytotoxicity. Tumor cells appeared to synthesize more polyglutamates than did the normal tissues examined. However, differences in total drug persistence and sensitivity to drug among tumor cells and among normal tissues did not reflect the relative extent of polyglutamate synthesis in each group. The extent of polyglutamate synthesis per se may not be a determinant of drug sensitivity in murine tissues. However, the accumulation of these metabolites may contribute in some way to overall therapeutic response or relative cytotoxicity.