Abstract
Studies of the uptake of methotrexate and an analogue, 4-amino-4-deoxy-N10-methylpteroic acid, which lacks the carboxy-L-glutamate moiety, suggest that these compounds are taken up by different processes. The methotrexate-resistant P1534 murine leukemia accumulated methotrexate 13 times more slowly than the drug-sensitive L1210 cell line. In contrast, uptake of 4-amino-4-deoxy-N10-methylpteroic acid proceeded at similar rates in both cell lines. Both compounds are potent inhibitors of the enzyme dihydrofolate reductase (5, 6, 7, 8-tetrahydrofolate: NADP-oxido reductase, EC 1.5.1.3. These findings suggest that drug resistance based on impaired uptake might be circumvented by the use of appropriate drug analogues.
ACKNOWLEDGMENTS Miss Marjorie Myers and Mrs. Judy Henrikson assisted with these studies.
- Copyright ©, 1969, by Academic Press Inc.
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