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A Mechanism of Resistance to Fluoropyrimidines^*

Alexander Bloch and Dorris J. Hutchison

( Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, and Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University Medical College, New York, N. Y.)

The requirements for amino acids, vitamins, pyrimidines, purines, and glucose of the sensitive Streptococcus faecalis (ATCC 8043) were compared with those of four mutants selected for their resistance to 5-fluorouracil, 5-fluorouridine, 5-fluoro-2'-deoxyuridine, and 5-fluoro-2'-deoxycytidine. The observed differences could be correlated with a shift toward the increased biosynthesis of metabolites which can reverse the growth inhibition caused by the active intermediate, 5-fluoro-2'-deoxyuridylic acid. The increase in the metabolic activity of a mutant is a reflection of the extent to which the corresponding analog is converted to the active intermediate. No differences in the rate of uptake of 5-fluorouracil were observed between the sensitive or resistant strains. Resistance to a fluoropyrimidine is accompanied by complete cross-resistance to the less potent fluoropyrimidines and by partial resistance toward the more potent fluoro-derivatives.

^* These studies were supported in part by Contract No. SA-43-ph-2445 from the Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health; and by Grant T-107 from the American Cancer Society. The senior author was a Predoctoral Fellow supported by training grant CRTY-5015 from the National Cancer Institute.

Present address: Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York.

Received 9/ 9/63.