EFFECTS OF BIZELESIN (U-77,779), A BIFUNCTIONAL ALKYLATING MINOR-GROOVE BINDER, ON REPLICATION OF GENOMIC AND SIMIAN-VIRUS-40 DNA IN BSC-1 CELLS

Bizelesin, an AT-specific DNA-alkylating antitumor drug, is a potent i nhibitor of genomic DNA replication in BSC-1 cells. Fifty percent inhi bition of DNA synthesis was observed at 10 nM bizelesin compared to 16 0 nM needed for 50% inhibition of RNA synthesis while no inhibition of protein synthesis was observed up to 200 nM, Sedimentation analysis o f nascent genomic DNA showed that bizelesin inhibited new replicon ini tiation and had significantly less effect on replicon maturation. Bize lesin also suppressed the intracellular synthesis of simian virus 40 ( SV40) DNA in virus-infected BSC-1 cells. The analysis of nascent SV40 intermediates synthesized after bizelesin treatment confirmed an initi ation-specific inhibition. The inhibitory effects on cellular DNA repl ication occurred at bizelesin levels resulting in infrequent adducts ( one adduct per several replicons). Only one bizelesin adduct per sever al SV40 molecules was needed for a potent inhibition of intracellular SV40 replication. In contrast, only partial inhibition of SV40 replica tion in vitro was observed with bizelesin-treated naked SV40 DNA as a template. Overall, the results indicate that infrequent bizelesin lesi ons impede the cellular replication apparatus at the level of the init iation of new replicons. (C) 1997 Elsevier Science B.V.