Effects of second-generation platinum analogs on isolated PM-2 DNA and their cytotoxicity in vitro and in vivo.
Using PM-2 DNA and cytotoxicity assay systems, we have studied several second-generation platinum analogs and compared these to the parent compound cis-diamminedichloroplatinum(II). These results indicate that all planar platinum(II) congeners induced similar effects upon interaction with PM-2 DNA, i.e., alteration of the tertiary DNA conformations. The reactivity of the analogs with DNA depended on the activity of the leaving groups. Octahedral platinum(IV) compounds, however, induced breakage of covalently closed circular PM-2 DNA, and the effects were not inhibited by either chloride or ethylenediaminetetraacetate. This suggests that breakage of isolated PM-2 DNA may be related to the axial trans bonds rather than the equatorial cis bonds of the solvated platinum(IV) compounds, since the activity of the dichloroplatinum(II) compounds has been shown to be inhibited by chloride ions. Studies on the in vitro and in vivo cytotoxicity of the platinum analogs demonstrated that the reactivity of analogs against PM-2 DNA correlated with in vitro and in vivo potencies. The reactivity with PM-2 DNA appeared to depend on the characteristics of the leaving group.
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival; D055598:Chemical Phenomena; D002621:Chemistry; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D004270:DNA, Circular / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D004279:DNA, Viral / Q000302:isolation & purification / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D007536:Isomerism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology; D010957:Plasmids; D013329:Structure-Activity Relationship
D004270:DNA, Circular; D004278:DNA, Superhelical; D004279:DNA, Viral; D009944:Organoplatinum Compounds; D002945:Cisplatin