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Mechanisms of Sensitivity and Resistance of Murine Tumors to 5-Fluorouracil

Laboratories of Toxicology [B. A., D. A. C., H. N. J.] and Medicinal Chemistry and Biology [C. K. C., R. I. G.], Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205, and Department of Medical Oncology, Georgetown University Hospital Medical School, Washington, D. C. 20007 [B. A., J.M., P.S.S.]

The biochemical basis for the resistance of murine leukemia P388 to 5-fluorouracil (FUra) was sytematically investigated by examining the transport and metabolism of FUra, or its anabolites, as well as the inhibition of enzymes and processes known to be affected by the drug. Of these parameters, only three were found to be altered significantly in the resistant line: (a) the enzyme required for the phosphorylation of uridine 5'-monophosphate to uridine 5'-diphosphate was present at a significantly lower specific activity in the resistant line than in its sensitive counterpart; (b) the rates of generation and persistance of 5-fluoro-2'-deoxyuridine 5'-monophosphate were significantly lower and shorter in the variant; and (c) there was a 1.6- and 3-fold decrease in the incorporation of FUra into polyadenylic acid-containing RNA and polyadenylic acid-lacking RNA, respectively, in resistant versus sensitive cells. Taken together, these findings suggest a dual mechanism for resistance to FUra in these leukemic cells, namely, a depressed capacity to generate di- and triphosphates of the riboside and deoxyriboside of the drug leading to lower pools of the proximate antimetabolite, fluorouridine 5'-triphosphate, and accelerated excretion of 5-fluoro-2'-deoxyuridine 5'-monophosphate, so that thymidylate synthetase is perturbed in a less than lethal way.

¹ To whom requests for reprints should be addressed, at City of Hope National Medical Center, 1500 East Duarte, Duarte, Calif. 91010.

² Fellow in the Pharmacology Research Associate Program, National Institute of General Medical Sciences, NIH.

Received 5/21/79. Accepted 1/25/80.

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