PACLITAXEL SENSITIZES MULTIDRUG-RESISTANT CELLS TO RADIATION

The unique action of paclitaxel, to stabilize microtubules and block c ells at the radiosensitive G(2)M phase of the cell cycle, suggests it may sensitize tumors to radiotherapy, We have investigated the potenti al of this interaction to overcome multidrug resistance in vitro using the HL60 cell line and its P-glycoprotein expressing, multidrug resis tant H/E8 subline. HL60 cells showed a modest 1.4-fold (p < 0.01) incr ease in sensitivity to 2 Gy radiation given 24 h after a 1 h treatment with paclitaxel, The H/E8 subline, which has increased radiation resi stance and expresses an extended multidrug resistance phenotype, showe d 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 G(2)/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 (greater than or equal t o 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.