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Comparative Study of the Thymidine Kinase and Thymidylate Kinase Activities and of the Feedback Inhibition of Thymidine Kinase in Normal and Neoplastic Human Tissue¹

Roswell Park Memorial Institute and The Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 14214

Activity levels of thymidine kinase and thymidylate kinase were determined in extracts from 23 matched human neoplastic and normal tissue pairs. Thymidine kinase activity was higher in the tumor than in the corresponding normal tissue, with two exceptions, bronchogenic carcinoma and hypernephroma. Thymidylate kinase activity was higher in the tumor than in the corresponding normal tissue in all cases.

Feedback inhibition of thymidine kinase activity has been studied in 17 of these pairs to date. Exogenous thymidine-5'-triphosphate (the end-product of the kinase reaction sequence) significantly inhibited the phosphorylation of thymidine in all of the tumor extracts to the same or even greater extent than in the corresponding normal tissue extracts. These results indicate that the feedback control mechanism of the "salvage" pathway for the synthesis of thymidine-5'-phosphates is operative in neoplastic tissues.

¹ This investigation was supported by Public Health Service Research Grants No. CA-05522, CA-06695, CA-07800, CA-05136, and 1-MO1-FR-00262 from the National Cancer Institute and by the American Cancer Society. A preliminary report on part of these results has been presented (24).

Received 8/17/67. Accepted 5/22/68.