3-Deazaguanine: inhibition of initiation of translation in L1210 cells.

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 inhibiton 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 profile inhibited the initiation of translation. This was confirmed by the demonstration of the inhibition of 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.