© 1999 by Society
© 1999 by the Society forNeuro-Oncology
Characterization of paclitaxel (Taxol®) sensitivity in human glioma-and medulloblastoma-derived cell lines
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 RegionalHospital and Medical Center, Seattle, WA 98105; Department of Neurological Surgery [M.S.Be.], University ofCalifornia, 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, 1959N.E. Pacific St., Seattle, WA 98195-6470.
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Abstract |
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Paclitaxel (Taxol®), a cytotoxic natural product that disruptsmicrotubule integrity, is being clinically evaluated for use against gliomas.We examined paclitaxel-induced killing in seven cell lines derived from humanmalignant astrocytic gliomas and medulloblastomas with the goal ofcharacterizing range of sensitivity, contribution of P-glycoprotein170–mediated drug efflux to resistance, and cross-resistance withalkylating agents. Exposure to paclitaxel for 8 h or less produced biphasicsurvival curves for all lines, with 40–75% of cells comprising asubpopulation that was 9–26 times more resistant to paclitaxel than themore sensitive fraction. Increasing exposure to 24 h eliminated the resistantsubpopulation, increasing sensitivity 50- to 400-fold. The dose producing onelog of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM,comparable to concentrations in the cerebrospinal fluid of brain tumorpatients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxeland either nimodipine or verapamil, inhibitors of P-glycoprotein activity, didnot increase sensitivity, demonstrating that thefivefold range in sensitivitywas not due to P-glycoprotein–mediated drug efflux. Importantly, therewas no correlation between LD10 for paclitaxel and LD10for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide,indicating no expression of cross-resistance to these different classes oftumoricidal agents. Our results suggest that greater clinical efficacy ofpaclitaxel against malignant brain tumors may be obtained by infusion for 24 hor longer and support the use of paclitaxel in combination with alkylatingagents.
Received August 3, 1998; Accepted October 22, 1998
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