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Effects of Derivatives of Cyclic 3',5'-Adenosine Monophosphate on the Growth, Morphology, and Gene Expression of Hepatoma Cells in Culture¹

Division of Research, National Jewish Hospital and Research Center [R. V. W., W. D. W.], and Department of Pharmacology, University of Colorado School of Medicine [K. C.], Denver, Colorado 80206

The growth rate of Reuber H35 hepatoma cells in monolayer culture has been shown to be inhibited by N⁶,O²'-dibutyryl cyclic 3',5'-adenosine monophosphate (DBcAMP). The effect is concentration dependent and readily reversible. Other adenine nucleotides are inactive at concentrations at which DBcAMP is active or cause release of cells into the medium and subsequent cell death at high concentrations. DBcAMP also exhibits similar toxicity at high concentrations, but only DBcAMP and two 8-thio derivatives of cyclic 3',5'-adenosine monophosphate appreciably reduce the growth of attached cells at any concentration. Cells grown in the presence of DBcAMP are larger and also possess characteristic long, narrow processes. HTC hepatoma cells do not exhibit any of these specific responses to DBcAMP, but they do show a nonspecific toxic response with high concentrations of DBcAMP and adenine nucleotides. Among the derivatives of cyclic 3',5'-adenosine monophosphatetested, only those that are effective inducers of tyrosine transaminase are capable of inhibiting the growth of attached H35 cells. The rate of protein synthesis was not inhibited by growth of H35 cells in the presence of DBcAMP and the content of protein was greater in the treated cells. In contrast, DNA synthesis was markedly inhibited shortly after the addition of DBcAMP. It is concluded that DBcAMP and certain derivatives of cyclic 3',5'-adenosine monophosphate are capable of specifically and reversibly inhibiting the growth of H35 hepatoma cells in culture.

¹ This work was supported by the Netherlands Organization for the Advancement of Pure Research (Z. W. O.), by Grant AM 14601 from the NIH, USPHS, and by General Research Support Grant RR 05474 to National Jewish Hospital from the same agency.

² On leave of absence from Van't Hoff Laboratory, State University, Utrecht, The Netherlands.

Received 2/18/72. Accepted 6/ 1/72.

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