cis-diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics

Cisplatin is an highly effective chemotherapeutic agent which produces a cumulative dose-limiting peripheral neuropathy. In this study, a possible role for microtubule abnormalities in cisplatin-induced toxicity was explored. CD rats (300 g) were injected daily ip with five doses of cisplatin (2 mg/kg) or every other day ip with two doses of cisplatin (10 mg/kg). The day after the last dose, the rats were killed and tubulin was purified from their testes. The maximal rate of cold-induced microtubule disassembly was consistently slower for testis tubulin purified from cisplatin-treated rats compared with control rats. Overnight in vitro coincubation of polymerized bovine brain tubulin with cisplatin followed by a purifying cycle of assembly and disassembly yielded tubulin capable of forming morphologically normal but short microtubules (average length: cisplatin-treated, 2.5 microns; control, 3.7 microns). Cisplatin coincubation markedly reduced the rate of cold-induced microtubule disassembly, producing a half-maximal effect at approximately 0.3 mM. The cold stability of cisplatin-treated microtubules could be partially reversed by diethyldithiocarbamate. Carboplatin, a cisplatin analog which does not cause clinical peripheral neuropathy, was less capable of producing microtubule disassembly abnormalities. These findings demonstrate the ability of cisplatin to alter microtubule disassembly by direct tubulin modification, an abnormality which may contribute to cisplatin-induced peripheral neuropathy.