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Leukemia. 1987 Feb;1(2):116-20.

Effects of methotrexate and of the "nonclassical" folate antagonist trimetrexate on human leukemia cells.

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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.


Twenty-five samples of fresh malignant cells of patients with acute leukemia (16 with acute myeloblastic leukemia, five with acute lymphoblastic leukemia, and four with chronic myelocytic leukemia in blast crisis) and of two patients with colon carcinoma were exposed for 1 hr to different concentrations of methotrexate (MTX) or trimetrexate (TMQ). In all samples, TMQ was at least one log more potent than MTX in inhibiting [3H]deoxyuridine incorporation into DNA. Cells relatively resistant in vitro to MTX also displayed decreased sensitivity to TMQ, although TMQ "resistance" was usually much less pronounced. In eight of the 25 leukemia samples, intracellular drug levels after exposure in vitro could also be measured. The intracellular levels of TMQ were 6 to 64 times higher than those of MTX, indicating that the difference in potency of these drugs may be related to the difference in intracellular accumulation. The intracellular levels of both agents varied widely and were not directly related to the degree of DNA synthesis inhibition. There was, however, a clear positive correlation between the intracellular ratio [TMQ]/[MTX] and the deoxyuridine incorporation after exposure to MTX. This observation suggests that 1) intracellular TMQ levels may be used as an internal standard to correct steady state intracellular MTX levels for variations such as cell size, and 2) in analogy to tissue-culture models, decreased intracellular accumulation of MTX may contribute to clinically encountered drug resistance.

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