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Rapid Arrest of DNA Synthesis by N⁶,O^2'-Dibutyryl Cyclic Adenosine 3',5'-Monophosphate in Cultured Hepatoma Cells¹

Division of Research, National Jewish Hospital and Research Center, Denver 80206 [R. V. W.], and Van't Hoff Laboratory, State University, Utrecht, The Netherlands [M. M. B., J. V. R.]

Mitotic index analyses after release of cultured Reuber H35 cells from a single thymidine blockade revealed that the inhibitory effects of N⁶,O^2'-dibutyryl cyclic adenosine 3',5'-monophosphate (DBcAMP) on the growth rate can be almost completely accounted for by a prolongation of the DNA-synthetic (S) phase in these cells. DBcAMP also led to a comparable lengthening of the interval during which deoxyadenosine-³H was incorporated into DNA after release from thymidine blockade. Incorporation of ³H-labeled deoxyribonucleosides into DNA is almost immediately inhibited by DBcAMP in interphase H35 cells. This inhibition can be equally as rapidly reversed upon withdrawal of the cyclic nucleotide analog. These results suggest that DBcAMP inhibits overall DNA synthesis and not just the initiation of replication. In addition, the incorporation of ³H-labeled thymidine and deoxycytidine did not provide a valid measure of the relative rates of DNA synthesis under certain conditions.

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, August 1971 to August 1972.

³ Present address: Department of Pharmacology, University of Colorado Medical Center, Denver, Colo. 80220.

Received 10/20/72. Accepted 3/ 9/73.