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Studies on the Mechanism of Human Tumor Resistance to the Fluorinated Pyrimidines^*

( Department of Surgery and Division of Clinical Oncology, The Medical School, University of Wisconsin, Madison, Wisconsin)

The in vitro effect of fluorinated pyrimidines on uridine and thymidine incorporation into DNA and the subsequent clinical responses to fluorinated pyrimidine chemotherapy was studied in 55 human tumors. In some cases tumor resistance was attributed to a deficiency of the enzymes which are required for converting 5-fluorouracil or 5-fluoro-2'-deoxyuridine to the active compound, 5-fluoro-2'-deoxyuridine-5-monophosphate. In other tumors where these enzymes were present but the incorporation of uridine and thymidine was not affected by the fluorinated pyrimidines, an insensitive thymidylate synthetase was implicated as the cause of tumor resistance. This report is an extension to human tumors of the work by other investigators who studied the problem of fluorinated pyrimidine resistance in experimental animal tumors.

^* This work was supported in part by grants CA05953 and CA06749 from the United States Public Health Service, National Institutes of Health, Bethesda, Maryland.

Received 4/ 2/64.