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Pediatric Experimental Therapeutics |
Department of Neurological Surgery [S.H.T., M.S.Bo., J.R.S.], University of Washington, Seattle, WA 98195-6470; Division of Neurosurgery [M.S.Bo.], Children's Regional Hospital and Medical Center, Seattle, WA 98105; Department of Neurological Surgery [M.S.Be.], University of California, Moffitt Hospital, San Francisco, CA 94143-0112
2 Address correspondence and reprint requests to John R. Silber, Ph.D., Department of Neurological Surgery, Box 356470, University of Washington, 1959 N.E. Pacific St., Seattle, WA 98195-6470.
Abstract
Paclitaxel (Taxol®), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of P-glycoprotein 170–mediated drug efflux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40–75% of cells comprising a subpopulation that was 9–26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50- to 400-fold. The dose producing one log of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal fluid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that thefivefold range in sensitivity was not due to P-glycoprotein–mediated drug efflux. Importantly, there was no correlation between LD10 for paclitaxel and LD10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical efficacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents.
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