Molecular Pharmacology, Vol 5, 21-25, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

A Comparison of 4-Amino-4-deoxy-N¹⁰-methylpteroic Acid and Methotrexate Transport by Mouse Leukemia Cells

¹ Laboratories of Pharmacology, Children’s Cancer Research Foundation, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

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.

Note:
ACKNOWLEDGMENTS Miss Marjorie Myers and Mrs. Judy Henrikson assisted with these studies.

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