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Dual Mechanisms of Inhibition of DNA Synthesis by Triciribine¹

Departments of Pharmaceutical Chemistry [L. L. W., L. M. J., K. Z. B.] and Medicinal Chemistry [L. B. T.], College of Pharmacy, Department of Chemistry [L. B. T.]; and Department of Internal Medicine-Nuclear Medicine, Medical School, The University of Michigan, Ann Arbor, Michigan 48109-1065 [D. L. G.]; Southern Research Institute, Birmingham, Alabama 35205 [W. B. P.]

The inhibition of DNA synthesis in triciribine (TCN)-treated L1210 cells was shown to involve two mechanisms, with different concentration dependence. (a) Initiation of new replicons and possibly of Okazaki fragments was inhibited when the cells were treated with 0.1 µM TCN. The inhibition of replicon initiation was shown by the rate of alkaline elution of [³H]DNA from 15-min-[³H]thymidine-labeled cells being slower if the cells had been pretreated with TCN, indicating that the average size of actively replicating DNA strands was increased. (b) At 1 µM TCN elongation of previously initiated DNA chains was also inhibited. This conclusion was suggested by the decrease in the rate of alkaline elution of [³H]DNA, during postlabeling incubation, being less if TCN was included in the medium. The mechanism of inhibition of DNA synthesis by TCN was shown not to involve DNA strand breakage or cross-linking, inhibition of polyamine biosynthesis, inhibition of purine de novo biosynthesis, inhibition of DNA polymerase or DNA primase, or inhibition of ligation of Okazaki fragments. The effects of TCN on the incorporation of [³H]thymidine into Okazaki fragments and higher molecular weight DNA suggested the possibilities of inhibition of Okazaki fragment initiation and/or DNA polymerase .

¹ This investigation was supported in part by Grant CH-310 from the American Cancer Society, by Grant CA34200-07 from the National Cancer Institute, and by a grant to L. L. W. from the Office of the Vice President for Research, University of Michigan.

² To whom requests for reprints should be addressed.

Received 1/18/90. Accepted 5/ 1/90.

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