Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines

Abstract

The antitumor activity of the trinuclear Phase I clinical agent, BBR3464, is matched by that of polyamine-linked dinuclear complexes. The cytotoxicity and cellular accumulation of three polynuclear platinum complexes: [{ trans-PtCl(NH 3) 2} 2μ-{ trans-Pt(NH 3) 2(H 2N(CH 2) 6NH 2) 2}] 4+ (BBR3464), [{ trans-PtCl(NH 3) 2} 2(H 2N(CH 2) 3NH 2(CH 2) 4NH 2)] 3+ (BBR3571), and [{ trans-PtCl(NH 3) 2} 2 (H 2N(CH 2) 6NH 2)] 2+ (BBR3005), were studied in a series of murine L1210 cell lines and compared with cisplatin. Besides murine L1210 cell lines sensitive (/0) and resistant (/DDP) to cisplatin, the efficacy of the compounds in a cell line rendered resistant to BBR3464 (/3464) was examined. Finally, to examine possible uptake pathways of these novel charged complexes, cytotoxicity in a cell line resistant to the polyamine synthesis inhibitor, methylglyoxal-bis(guanylhydrazone) (/MGBG), was studied. Cytotoxicity profiles of BBR3571 most closely matched that of BBR3464. Both agents showed significantly reduced cytotoxicity in L1210/BBR3464. The cytotoxicity of neither agent was affected by the polyamine uptake-deficient cell line and indeed both complexes showed significantly enhanced cytotoxicity in L1210/MGBG relative to wild-type L1210/0. The cellular uptake of both BBR3464 and BBR3571 was enhanced in L1210/DDP. These studies suggest that the chemical feature of a diamine linker containing an internal charge contributes significantly to the anticancer profiles of both the trinuclear platinum complex, BBR3464, which incorporates a charged platinum into a diamine linker, and the dinuclear platinum complex, BBR3571, which incorporates only a naturally occurring polyamine as diamine linker.