Paclitaxel-induced cytotoxicity--the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein.
Paclitaxel (Taxol) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.
Fjällskog
M L
ML
Department of Oncology, University of Uppsala, Akademiska sjukhuset, Sweden.
Frii
L
L
Bergh
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D012997:Solvents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012997:Solvents; D000431:Ethanol; C000515:cremophor EL; D004317:Doxorubicin; D017239:Paclitaxel; D005990:Glycerol