INHIBITION OF MAMMALIAN DNA POLYMERASE-ASSOCIATED 3' TO 5' EXONUCLEASE ACTIVITY BY 5'-MONOPHOSPHATES OF 3'-AZIDO-3'-DEOXYTHYMIDINE AND 3'-AMINO-3'-DEOXYTHYMIDINE

3'-Azido-3'-deoxythymidine 5'-monophosphate (AZT-MP) has been hypothes ized by us to possibly affect 3'-azido-3'-deoxythymidine (AZT) excisio n from host cell DNA. In the present study, AZT-MP inhibited 3' to 5' exonuclease activity of calf thymus DNA polymerase delta at pharmacolo gical relevant intracellular concentrations. Other 2',3'-dideoxynucleo side-5'-monophosphate (ddN-MP) analogs, including 3'-amino-3'-deoxythy midine-5'-monophosphate (AMT-MP), were also assayed as potential inhib itors of 3' to 5' exonuclease activity. Tle monophosphate derivative o f 3'-amino-3'-deoxythymidine (AMT), an in vivo toxic catabolite of AZT , was the most potent of the ddN-MP analogs tested, inhibiting this ac tivity by more than 50% at 100 muM. These results suggest that inhibit ion of 3' to 5' exonuclease activities by AZT-MP and AMT-MP may increa se steady-state levels of AZT in host DNA, accounting in part for the cell toxicity associated with this drug. The present study also raises the question of whether AZT-MP inhibition of this activity may lead t o potential mutagenic effects due to inhibition of 3' to 5' exonucleas e-mediated proofreading functions involved in DNA replication.