Cellular pharmacology of polynuclear platinum anti-cancer agents

Abstract

Study of the cellular pharmacology of the dinuclear platinum complexes, BBR3005 ([{ trans-PtCl(NH 3) 2} 2H 2N(CH 2) 6NH 2] 2+), BBR3171 ([{ cis-PtCl(NH 3) 2} 2H 2N(CH 2) 6NH 2] 2+) and the trinuclear platinum complex, BBR3464 ([{ trans-PtCl(NH 3) 2} 2μ-{trans-Pt(NH 3) 2(H 2N(CH 2) 6NH 2) 2}] 4+) was undertaken in wild type and cisplatin-resistant L1210 murine leukemia cell lines. All complexes are potent cytotoxic agents against the wild type cell line. Only BBR3464 shows enhanced activity against the cisplatin-resistant cell line following a brief exposure. This enhanced activity is attributable, in part, to preserved accumulation, which contrasts with diminished accumulation of cisplatin and both dinuclear platinum complexes. The cisplatin-resistant cell line is relatively tolerant of DNA adducts induced by both cisplatin and BBR3464, but BBR3464 is much less affected. All complexes induce DNA interstrand cross-links. Di/trinuclear complex-induced interstrand cross-linking peaks early, suggesting rapid genomic access and interaction. Subsequent decay suggests susceptibility to DNA repair mechanisms. Peak and area-under-the-curve values for interstrand cross-linking among the complexes correlate poorly with cytotoxic effects, especially in the cisplatin-resistant cell line. This suggests that all interstrand cross-linking adducts are not equal in their cytotoxic effect, or other, non-interstrand cross-linking adducts are significant. BBR3464 has been selected for clinical development largely on the basis of results from in vivo activity and toxicity studies. These results show BBR3464 to have unique properties in the context of acquired cisplatin-resistance that enhance its candidacy as a potential anticancer agent.