Fellner, Stephan and Bauer, Bjoern and Miller, David S. and Schaffrik, Martina and Fankhaenel, Martina and Spruss, Thilo and Bernhardt, Guenther and Graeff, Claudia and Faerber, Lothar and Gschaidmeier, Harald and Buschauer, Armin and Fricker, Gert (2002) Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo. JOURNAL OF CLINICAL INVESTIGATION, 110 (9). pp. 1309-1318. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. in vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C-4 (LTC4), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RESISTANCE-ASSOCIATED PROTEIN; P-GLYCOPROTEIN; ENDOTHELIAL-CELLS; ORAL BIOAVAILABILITY; SOLID TUMORS; LUNG-CANCER; STAGE-III; PSC 833; EXPRESSION; MICE; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2021 05:40 |
| Last Modified: | 04 Oct 2021 05:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/39735 |
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