Overcoming of cross-resistance to the cell-killing activity of oxygen radicals in VCR-resistant hematologic cell lines with cyclosporin-A.
Anti-cancer agents like adriamycin, mitomycin-C, bleomycin, and etoposide express their cell-killing activity partly through oxygen radicals. Since vincristine (VCR)-resistant cells show cross-resistance to oxygen radicals, this study was designed to study whether the combined effects of oxygen radicals derived from hypoxanthine-xanthine oxidase plus enhancers of anti-cancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxygen radicals in VCR-resistant human leukemia/lymphoma cell lines. We found that 3 micrograms/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 lines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cidal activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms from those of Ver or Dip, and Cy-A may be useful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment.
Division of Laboratory Medicine, School of Dentistry, University of Tokushima, Japan.
S
S
Hamano
M
M
Hirose
E
E
Hosoi
H
H
Houchi
Y
Y
Kuroda
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005609:Free Radicals; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia; D008223:Lymphoma; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000633:toxicity*; D014969:Xanthine Oxidase / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005609:Free Radicals; D012333:RNA, Messenger; D014750:Vincristine; D004176:Dipyridamole; D016572:Cyclosporine; D014700:Verapamil; D014969:Xanthine Oxidase