Modulation of doxorubicin-induced DNA lesions by verapamil, DMDP and dipyridamole in resistant P388 cell lines.
Lymphoid cell lines resistant to doxorubicin, P388/R, were characterized by: 1) decreased intracellular acumulatin and retention of DOX; 2) decreased amount of DOX-induced DNA lesions; and 3) rapid repair of DOX-induced DNA lesions. Using the highest noncytotoxic concentrations of three modulators; 2 calcium channel blockers, Verapamil (VEP) and DMDP and a nucleoside transport inhibitor, Dipyridamole (DIP), restoration of Doxorubicin (DOX) sensitivity in vitro against P388/R cells was partial; resistance was reduced from approximately 200 to 10 fold, although DOX accumulation in the resistant cells in the presence of the modulators was completely restored. The DNA single-strand break (SSB) level induced by DOX in P388/S cells (1371 +/- 144 rad equivalents) was significantly higher than in P388/R cells (74 +/- 17 rad equivalents). The effects of VEP, DMDP and DIP on the induction of DNA SSBs by DOX in P388/R were different. DMDP and DIP potentiated the DOX-induced DNA SSBs by 30% each and VEP by 15%. Furthermore, while VEP and DIP had no significant effects on the rapid repair of DOX-induced SSBs, no significant repair of DNA lesion was observed in P388/R treated with DMDP at 1.2 microM, a non-cytotoxic concentration. These data indicate that although these modulators can effectively restore the intracellular accumulation and retention of DOX, these conditions although essential are not sufficient for the complete restoration of DOX sensitivity in this highly resistant cll line. The ability of a calcium antagonist, DMDP, to circumvent DOX resistance might be related not only to the modulation of drug retention, but also to the ability to retard the repair of DOX-induced DNA SSBs.
Yin
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Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
Bankusli
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I
Frank
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Rustum
Y M
YM
D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004176:Dipyridamole / Q000378:metabolism / Q000494:pharmacology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D050113:Imino Furanoses; D007941:Leukemia P388 / Q000235:genetics / Q000378:metabolism; D008353:Mannitol / Q000031:analogs & derivatives; D011759:Pyrrolidines; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology*
D000470:Alkaloids; D004273:DNA, Neoplasm; D050113:Imino Furanoses; D011759:Pyrrolidines; D008353:Mannitol; C043121:2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine; D004176:Dipyridamole; D004317:Doxorubicin; D014700:Verapamil