Circumvention of Vincristine Resistance in Mice with In Vivo

A novel compound partially analogous to nifedipine, AHC-52, was found to sensitize multidrug-resistant tumor cells. AHC-52 at 0.5 MK/nil completely reversed the in vitro resistance to vincristine (VCR) in VCRresistant P388 cells (P388/VCR). Of various regimens examined for the in vivo treatment of P388/VCR-bearing mice, the combination of 0.05 mg/kg of VCR with 100 mg/kg twice a day of AHC-52 daily demonstrated the best result with a 206% increase in life prolongation. This result was comparable with that observed in parental P388-bearing mice treated with the optimal dose of VCR alone, indicating almost complete circum vention of resistance by combination VCR-AHC-52 therapy. In addition, the combination of both agents exhibited therapeutic effects in the treatment of P388-bearing mice with some long term survivors. This result was presumably due to the elimination of heterogeneity of VCR sensitivity in this cell population. These results suggest that combination chemotherapy using a sensitizing agent such as AHC-52 will be effective in not only circumvention of multidrug resistance but also retardation of its occurrence.