Cremophor-EL enhances taxol efficacy in a multi-drug resistant C1300 neuroblastoma cell line.
We have previously developed a homoharringtonine (HHT) resistant murine C1300 neuroblastoma cell line with increased p-glycoprotein expression and cross resistance to Adriamycin. Drug resistance in this cell line was reversed using cyclosporin-A, dipyridamole and cremophor-EL (CRE). Because of the high CRE content of parenteral taxol, we examined the ability of this solvent to reverse taxol cross-resistance in this cell line. Comparative ID-50s using clonogenic assays in agar indicate a 214-fold resistance to HHT. CRE reverses taxol cross-resistance in a dose-dependent manner from 0.003 to 0.1%, and is maximally effective at a subtoxic concentration of 0.03%. High pressure liquid chromatography (HPLC) analysis of taxol treated C1300/HHT cells reveal that CRE causes changes in intracellular drug levels that are not related to drug efflux. Our work shows that clinical preparations of taxol, when diluted to effective doses, contain enough CRE to mitigate multi-drug resistance. Clinical successes of taxol in refractory tumors may be due in part to the ability of its CRE base to reverse multi-drug resistance.
Chervinsky
D S
DS
Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York 14263.
Brecher
M L
ML
Hoelcle
M J
MJ
D000818:Animals; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles / Q000494:pharmacology*; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol