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3-Deazaguanine: Inhibition of Initiation of Translation in L1210 Cells¹

Departments of Pharmacology [R. S. R. H. G. M.] and Biochemistry [D. I.], The George Washington University Medical Center, Washington, D. C. 20037

In L1210 cells in culture, 3-deazaguanine (DG), a relatively new purine analog, was found to inhibit DNA and protein synthesis but not total RNA synthesis. The effect of the drug on protein synthesis was therefore further examined. Polyadenylic acid-containing RNA synthesis was not decreased by DG treatment, suggesting that the inhibition of protein synthesis was a function of an alteration in the process of translation. DG altered the polyribosome sedimentation profile in a dose-dependent manner, increasing the numbers of monosomes and smaller polysomes and decreasing the number of larger polysomes. The nascent polypeptides in DG-treated cells were labeled with [³H]leucine, and the increased number of monosomes was not associated with a proportionate amount of [³H]leucine when compared to the polysomes. This indicated that the monosomes had not been derived directly from the breakdown of active polysomes. The shift in the polysome profile was reversed by cycloheximide, suggesting that DG inhibited the initiation of translation. This was confirmed by the demonstration of the inhibition by DG of the formation of the 43S preinitiation complex. The inhibition of the initiation of protein synthesis by DG may contribute to the antitumor actions of this new purine analog.

¹ This investigation was supported by USPHS Grants CA-02978 and CA-27553 and Training Grant 5-T-32-CA-09223, awarded by the National Cancer Institute, Department of Health & Human Services.

² National Cancer Institute Trainee (Grant 5-T-32-CA-09223). Present address: Department of Pharmacology, Yale University School of Medicine, New Haven, Conn. 06510. From a dissertation presented to the Department of Pharmacology, The Graduate School of Arts and Sciences, The George Washington University, in partial fulfillment of the requirements for the Ph.D.

³ To whom requests for reprints should be addressed.

Received 11/17/81. Accepted 7/ 1/82.