Alteration and activation of sequence-specific cleavage of DNA by bleomycin in the presence of the antitumor drug cis-diamminedichloroplatinum(II).

Abstract

The antitumor drug cis-diamminedichloroplatinum(II) dramatically alters the sequence-specific cleavage of the bleomycin A2-iron(II)-O2 system. Preferred bleomycin cleavage sites adjacent to oligo(dG) regions on two restriction fragments of plasmid pBR322 DNA were masked by pretreatment with cis-diamminedichloroplatinum(II). trans-Diamminedichloroplatinum(II), which is inactive as an antitumor drug, showed similar but not identical behavior. The DNA-cleaving activity of bleomycin was substantially modified by cis-diamminedichloroplatinum(II), and a number of specific new cutting sites in guanine-rich parts of the sequence were activated by both isomers of the platinum complex. The results further emphasize the possibility that the synergism found when cis-diamminedichloroplatinum(II) and bleomycin are used in combination chemotherapy may be due to interactions at the level of DNA-drug binding.