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Interaction Drugs Inhibiting Different Steps in the Synthesis of DNA¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14203

Several inhibitors of DNA synthesis which could be expected to act at sequential or concurrent steps were studied alone and in combination to detect any increased effectiveness with suspension cultures of leukemia L1210. The type of interaction was interpreted by comparing the concentrations of each drug, alone and in combination, required to achieve 50% inhibition of growth after 42 hr of incubation, with the use of an isobologram for each pair of inhibitors to disclose synergistic, additive or antagonistic effects. The combination of 1-ß-D-arabinofuranosylcytosine (ara-C) with either methotrexate (MTX) or 5-fluorodeoxyuridine (FUdR) showed strong antagonism. Combination of 1-formylisoquinoline thiosemicarbazone (IQ-1) with MTX yielded slight antagonism, while the combination of IQ-1 with FUdR was additive or slightly synergistic. The combination of 9-ß-D-arabinofuranosyladenine with MTX was antagonistic, whereas the combination of 9-ß-D-arabinofuranosyladenine with FUdR was additive. Also, the combination of 9-ß-D-arabinofuranosyladenine with either IQ-1 or ara-C was additive.

The difference between the effects of IQ-1 and ara-C in combination with either MTX or FUdR strongly implies that the former drugs act by different mechanisms. These observations support the interpretation that the primary site of action of ara-C in these growing cells is not inhibition of ribonucleotide reductase. The various interactions observed in this study were quite unpredictable and could not be explained by the present concepts concerning combination chemotherapy.

¹ This investigation was supported in part by USPHS Research Grant CA-11047. The work reported herein was submitted by G. B. Grindey in partial fulfillment of the requirements for the Ph.D. degree in a cooperative program between the Program of Pharmacology, Roswell Park Memorial Institute, Division of the Graduate School, and the Department of Pharmacology, School of Medicine, State University of New York at Buffalo. A graduate fellowship from the New York State Department of Health supported G. B. Grindey.

² Present address: Wellcome Research Laboratories, 3030 Cornwallis Road, Research Triangle Park, N.C. 27709.

Received 7/13/71. Accepted 12/ 3/71.

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