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Behavior of Opposing Pathways of Thymidine Utilization in Differentiating, Regenerating, and Neoplastic Liver¹

Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [J. A. F., G. W.], and Department of Biochemistry, Howard University College of Medicine, Washington, D. C. 20001 [H. P. M.]

The behavior of opposing pathways of thymidine utilization was compared in proliferating normal liver (from developing rats and from partially hepatectomized rats) and in neoplastic liver (spectrum of hepatomas of different growth rates). The studies were carried out by assaying simultaneously the incorporation of labeled thymidine into DNA (synthetic pathway) and the degradation to CO₂ (catabolic pathway) in tissue slices in an in vitro system.

In the liver of newborn rats, the incorporation of thymidine into DNA is very high and gradually decreases during differentiation to very low levels in the adult. The catabolic utilization of thymidine is high in the newborn rat liver, and it further increases during differentiation, being approximately twice as high in the adult as in the newborn. The rise in the activity of the catabolic pathway is blocked by administration of actinomycin.

Partial hepatectomy results in marked changes in the behavior of thymidine metabolism. The activity of the synthetic pathway increases, while the activity of the catabolic pathway decreases. The increased activity of the synthetic pathway decreases to normal range and the decreased activity of the catabolic pathway returns to high levels about 96 hr after the operation.

In the hepatoma spectrum, the activity of the synthetic pathway increases and that of the catabolic pathway decreases parallel with the increase in tumor growth rate. As a result, there is a pronounced increase in the ratio of synthetic: catabolic utilization of thymidine, which shows a close correlation with hepatoma growth rate. The close linking of hepatoma growth rate with the behavior of the activities of opposing pathways of thymidine utilization and of the key enzymes of the pathways provides further evidence in support of the Molecular Correlation Concept.

¹ Supported by USPHS Grant CA-05034, an American Cancer Society Grant, a Damon Runyon Memorial Fund, Inc., grant (G. W.), and USPHS Grant CA-10729 (H. P. M.).

² To whom requests for reprints should be sent, at the Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Ind. 46202.

Received 9/ 2/70. Accepted 1/ 4/71.

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