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Growth Inhibition of a Spectrum of Transplanted Mouse Tumors by Combinations of Inhibitors of Nucleic Acid biosynthesis and Alkylating Agents^*

( Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut)

The tumor-inhibitory potency of combinations of uracil mustard and 6-thioguanine was measured in seven transplanted mouse neoplasms; pronounced inhibition occurred in five of the tumors. Maximum effectiveness of the combination occurred when simultaneous administration of the two drugs was employed; separation of dosages by an interval of 12 hours resulted in a marked reduction in activity. A monofunctional uracil mustard was not inhibitory by itself, nor did it enhance the tumor-inhibitory potency of 6-thioguanine in Sarcoma 180, a neoplasm sensitive to the difunctional mustard.

5-Fluorouracil, 5-iodo-2'-deoxyuridine, and 6-chloropurine potentiated the carcinolytic effects of uracil mustard; at the dose levels employed, 5-iodo-2'-deoxycytidine and 6-mercaptopurine produced borderline results, whereas 8-azaguanine, 6-azauridine, and azaserine did not enhance the tumor-inhibitory activity of uracil mustard on Sarcoma 180. Nitrogen mustard-thioguanine combinations produced at least an additive effect, whereas cyclophosphamide, chlorambucil, thio TEPA¹ and Myleran did not add to the 6-thioguanine-induced inhibition of this neoplasm.

^* This research was supported by a grant (CA-02817) from the National Cancer Institute, Public Health Service.

¹ The following abbreviations are used: DNA, deoxyribonucleic acid; RNA, ribonucleic acid; thioTEPA, N,N',N''-triethylenethiophosphoramide; Myleran, 1,4-(dimethanesulfonoxy)butane; chlorambucil, p-N,N-di(ß-chloroethyl)aminophenylbutyric acid; nitrogen mustard, methylbis(ß-chloroethyl)amine; cyclophosphamide, N,N-bis(ß-chloroethyl)-N', O-propylenephosphoric acid ester diamide; dopan, 5-[bis(ß-chloroethyl)amino]-6-methyluracil.

Received 6/20/63.