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Effects of Cortisol on DNA Metabolism in the Sensitive and Resistant Lines of Mouse Lymphoma P1798

Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York 14203

Administration of cortisol to mice bearing the cortisolsensitive or -resistant lines of lymphosarcoma P1798 resulted in a marked inhibition of incorporation of labeled deoxynucleoside precursors into tumor DNA only in the sensitive tumor. This effect is one of the earliest biochemical changes seen in lymphosarcoma P1798 following glucocorticoid treatment. It is dependent on both time and dose and is specific for steroids with glucocorticoid activity. A comparison of the incorporation of all 4 normally occurring deoxynucleoside precursors into DNA was made; thymidine was incorporated to the greatest extent, followed by deoxycytidine, deoxyguanosine, and deoxyadenosine. The characteristics of P1798 DNA polymerase were studied, and it was observed that the activity of this enzyme was not altered in the sensitive tumor at a time when there was a marked depression in the uptake of thymidine-³H into DNA. Also, the cortisol-induced inhibition of incorporation of labeled precursors into DNA could not be explained by a decreased uptake of the precursor into the cell or an increase in precursor pool size. The latter possibility was eliminated in studies which showed that a several thousand-fold variation in the specific activity of administered thymidine-³H failed to abolish the inhibitory action of cortisol on precursor incorporation into DNA, and by evidence indicating that there was no significant release of thymidine-³H from prelabeled tumor DNA following hormone treatment.

¹ NIH Predoctoral Fellow, Grant FO1 GM-41,359. The studies reported in this paper were taken from a thesis submitted by J. M. Rosen to the State University of New York at Buffalo, in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

² Supported by NIH Grant CA-05671 and Damon Runyon Grant DRG-982.

Received 8/26/69. Accepted 10/23/69.