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Studies with Mustards. VI. Effects of Alkylating Agents upon Nucleic Acid Synthesis in Bilaterally Grown Sensitive and Resistant Tumors^*

( Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama)

Administration of cyclophosphamide, methylbis(ß-chloroethyl)amine hydrochloride, 2,4,6-tris(1-aziridinyl) s-triazine, or triethylenethiophosphoramide to hamsters bearing bilaterally implanted cyclophosphamide-sensitive and cyclophosphamideresistant plasmacytomas caused regression of the sensitive tumors, whereas the resistant tumors continued to grow.

Incorporation of C¹⁴ from formate-C¹⁴ into the purines of RNA and DNA was inhibited by these agents in the sensitive tumors but not in the resistant tumors. The decreases in the specific activity of the nucleic acid purines corresponded to decreases in the total radioactivity of alcoholic extracts of the tumors; although there was a sizable decrease in the total activity of the extract, there were only small alterations in the distribution of the activity among the components of the extract-namely, small decreases in the portion of the C¹⁴ in the purines and purine-containing compounds and small increases in the portion of the C¹⁴ in serine and lactic acid.

The incorporation of adenine-8-C¹⁴ into the DNA of the sensitive tumor was inhibited by these agents, but incorporation into the RNA was not inhibited. There was no inhibition of incorporation of adenine-8-C¹⁴ into either the DNA or the RNA of the resistant tumor. Neither the total activity of the extracts nor the distribution of the activity among the components of the extracts of either the sensitive or the resistant tumor was significantly altered by these agents.

The data indicate that these agents interfered with the de novo synthesis of ribonucleotides but did not interfere with the conversion of adenine to ribonucleotides. There was also interference with the conversion of ribonucleotides to components of DNA but not of RNA.

Since similar results were obtained in in vitro experiments with HN2 and with minces of growing sensitive and resistant plasmacytomas, it seems probable that the observed inhibitory effects are related to the mode of action of the agents and are not simply characteristic of regressing tumors.

^* This investigation was supported by the Cancer Chemotherapy National Service Center, National Cancer Institute, under the National Institutes of Health Contract No. SA-43-ph-2433, and by grants from the Alfred P. Sloan Foundation and The John A. Hartford Foundation, Inc.

Affiliated with Sloan-Kettering Institute for Cancer Research, New York, N. Y.

Received 2/14/64.