Neuroprotective interactions in rats between paclitaxel and cisplatin

Paclitaxel and cisplatin are associated with dose-limiting neurotoxicity th at may result from their differing effects on microtubule stability in peri pheral nerves. We hypothesized that such different actions of paclitaxel an d cisplatin could be exploited to minimize their neurotoxicity by giving th em in combination. Paclitaxel (9-18 mu mol/kg/week or 7.7-15.4 mg/kg/week) and cisplatin (5-10 mu mol/kg/week or 1.5-3 mg/kg/week) were given alone an d in combination to female Wistar rats. Treatment was given once per week f or a total of 7-10 weeks. Paclitaxel and cisplatin were given 24 h apart wh en they were given in combination. Changes in sensory nerve conduction velo city (SNCV) and dorsal root ganglia (DRG) morphology were measured. The nat ure of their interaction was analyzed using an isobologram. Their antitumor activity alone or in combination was also determined in C57B1/6 mice beari ng colon 38 tumors. Reductions in SNCV occurred with paclitaxel alone (P = 0.009), cisplatin alone (P = 0.012), and cisplatin given 24 h before paclit axel (P < 0.0001). In contrast, there was no significant change in SNCV wit h paclitaxel given 24 h before cisplatin (P = 0.11). An isobologram showed that the SNCV effects of the drug combinations were less than additive or a ntagonistic. Cisplatin-induced morphometric changes in DRG neurons were les s marked when cisplatin was given with paclitaxel (P = 0.004). Concentratio ns of platinum in dorsal root ganglia, sural nerves, and sciatic nerves wer e not altered by giving paclitaxel before cisplatin. Tumor growth delays (T GD) were greater after treatment with paclitaxel (23.4 mu mol/kg or 20 mg/k g) given 24 h before cisplatin (23.3 mu mol/kg or 7 mg/kg) (TGD = 7.5 days) than after paclitaxel (23.4 mu mol/kg or 20 mg/kg) (TGD = 2.0 days) or cis platin (23.3 mu mol/kg or 7 mg/kg) (TGD = 3.5 days) alone. Paclitaxel and c isplatin antagonized each other's neurotoxicity in Wistar rats. Combining c ytotoxic agents with opposing effects on peripheral nerves has potential fo r minimizing neurotoxicity in patients.