OVERCOMING OF CROSS-RESISTANCE TO THE CELL-KILLING ACTIVITY OF OXYGENRADICALS IN VCR-RESISTANT HEMATOLOGIC CELL-LINES WITH CYCLOSPORINE-A

Anti-cancer agents like adriamycin, mitomycin-C, bleomycin, and etopos ide express their cell-killing activity pal?ly through oxygen radicals . Since vincristine (VCR)-resistant cells show cross-resistance to oxy gen radicals, this study was designed to study whether the combined ef fects bf oxygen radicals derived from hypoxanthine-xanthine oxidase pl us enhancers of anticancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxy gen radicals in VCR-resistant human leukemia/lymphoma cell lines. We f ound that 3 mu g/mL Cy-A enhances the cidal effect of oxygen radicals on two of five types of wild type and two of five VCR-resistant cell l ines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cida l activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms fi om those of Vet or Dip, and Cy-A may be u seful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment.