EFFECTS OF 2ND-GENERATION PLATINUM ANALOGS ON ISOLATED PM-2 DNA AND THEIR CYTO-TOXICITY INVITRO AND INVIVO

Abstract

Using PM-2 DNA and cytotoxicity assay systems, several 2nd-generation platinum analogs were compared to the parent compound cis-diamminedichloroplatinum(II) [an antineoplastic drug]. 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 dependended on the activity of the leaving groups. Octahedral plantinum(IV) compounds induced breakage of covalently closed PM-2 DNA, and the effects were not inhibited by chloride or ethylenediaminetetraacetate. 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 was inhibited by chloride ions. The reactivity of the platinum analogs against PM-2 DNA correlated with in vitro and in vivo cytotoxic potencies [against rat Novikoff hepatoma ascites cells]. The reactivity with PM-2 DNA appeared to depend on the characteristics of the leaving group.