Paclitaxel sensitizes multidrug resistant cells to radiation.
The unique action of paclitaxel, to stabilize microtubules and block cells at the radiosensitive G2M phase of the cell cycle, suggests, it may sensitize tumors to radiotherapy. We have investigated the potential of this interaction to overcome multidrug resistance in vitro using the HL60 cell line and its P-glycoprotein expressing, multidrug resistant H/E8 subline. HL60 cells showed a modest 1.4-fold (p < 0.01) increase in sensitivity to 2 Gy radiation given 24 h after a 1 h treatment with paclitaxel. The H/E8 subline, which has increased radiation resistance and expresses an extended multidrug resistance phenotype, showed significant sensitization to radiation (up to 2.3-fold sensitization; p < 0.01) even with doses of paclitaxel which had no effect on cell viability or were associated with any G2/M block in the cell cycle. In the presence of verapamil, an inhibitor of P-glycoprotein mediated efflux, drug resistant cells could be sensitized to 2 Gy radiation by similar paclitaxel doses as the parental cell (> or = 30 nM; p < 0.01). These results indicate a therapeutic advantage may be possible in the treatment of resistant tumors by the combined use of paclitaxel with radiation.
Mote
P A
PA
Neurobiology Unit, University of Technology, Sydney, NSW, Australia.
Davey
M W
MW
Davey
R A
RA
Oliver
L
L
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D017239:Paclitaxel / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D014700:Verapamil; D017239:Paclitaxel