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Effects of 6-Thioguanine on RNA Biosynthesis in Regenerating Rat Liver¹

Department of Pharmacology and Section of Developmental Therapeutics, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

6-Thioguanine, at a dose of 40 mg/kg body weight, was administered to rats at 12 hr after partial hepatectomy; 6 hr later, liver polysomes and cell sap were isolated and utilized to measure the effects of this antimetabolite on protein synthesis in vitro. When radioactive leucine was used to label peptides synthesized in vitro, no difference was observed between polyacrylamide gradient gel scans of systems derived from control regenerating liver and those from 6-thioguanine-treated regenerating liver. However, when radioactive tyrosine was used as the tracer to monitor synthesized peptides, a depression in the 30,000-molecular weight region of scans of products synthesized in systems derived from 6-thioguanine-treated regenerating liver was observed. Recombination experiments showed this effect to be due to the polysome component of the system. When equal amounts of polyadenylic acid-containing RNA from 6-thioguanine-treated or control regenerating liver were added to a wheat germ in vitro protein-synthesizing system, polyacrylamide gel scans of the products synthesized in the presence of radioactive tyrosine showed that more peptides were synthesized from polyadenylic acid-containing RNA from 6-thioguanine-treated rats than from control polyadenylic acid-containing RNA. That this phenomenon might be the result of incorporation of the analog into RNA was shown by the finding that all types of RNA contained 6-thioguanine, with the greatest concentration occurring in polyadenylic acid-containing RNA.

¹ Support was provided by Grants CA-02817 and CA-16354 from the National Cancer Institute, USPHS.

² Recipient of Training Grant GM-0059 from the General Medical Sciences, USPHS. The work described in this report is a portion of the work presented in partial fulfillment of the requirements for the Ph.D. degree.

Received 1/14/77. Accepted 3/21/77.