Cell line and schedule-dependent cytotoxicity of paclitaxel (Taxol): role of the solvent Cremophor EL/ethanol.
BACKGROUND
Paclitaxel's optimal dosage and scheduling is currently not determined. To compare paclitaxel (PTX) cytotoxicity in vitro, three cell lines were chosen for investigation by single versus fractionated exposure to Taxol and the diluent Cremophor EL/ethanol (CEL/eth).


METHODS
An exponentially growing human lung-carcinoma (SK-LU-1), human glioblastoma (U-138 MG) and mammalian fibroblast cell line (HyB14FAF28) were used for colony forming assay examining cell survival, and flow cytometric DNA analysis by measuring cell cycle development. Tested concentrations varied from 2-50 microM and were incubated for 3 and 15 hours. Single (2-50 microM/d, especially 10 microM/d), versus fractionated (2 microM/d, day 1-5) exposure of Taxol and CEL/eth was investigated. As the control population, cells were exposed to a phosphate buffered solution (PBS).


RESULTS
Control populations demonstrated an average survival of 90, 99 and 93% for SK-LU-1, U-138 MG, B14, respectively. Single Taxol exposure at 10 microM showed average survival of 54, 50 and 84% after 3 hours and 9, 48 and 82% after 15 hours for the above cell lines. Fractionated Taxol exposure with 2 microM/d, days 1-5 led to average survival of 55, 86 and 63%, respectively. Single CEL/eth exposure showed a cytotoxic effect with average survival of 94, 126 and 91% after 3 hours and 47, 63 and 88% after 15 hours respectively. Fractionated CEL/eth exposure showed an average survival of 67, 94 and 65% respectively. Flow cytometric analysis detected cell cycle shift concerning S- and G2/M-phase after Taxol exposure only in the two tumour cell lines, and not in the fibroblastic cells. CEL/eth was without significant effect on cell cycle distribution in all three cell lines.


CONCLUSIONS
In the two human tumour cell lines cytotoxicity was more pronounced after prolonged Taxol exposure. The fibroblast cell line was not sensitive to single treatment, and was without cell cycle changes. Comparable to Taxol the diluent CEL/eth had a significant but less pronounced cytotoxic effect. Therefore, the cytotoxic mechanisms of paclitaxel's and CEL/eth's are worthy of further investigation.
Cordes
N
N
Department of Radiation-Oncology, University Hospitals, Erlangen-Nuernberg, Germany.
Plasswilm
L
L
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D000431:Ethanol / Q000494:pharmacology*; D005347:Fibroblasts; D005434:Flow Cytometry / Q000379:methods; D005909:Glioblastoma; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D008322:Mammals; D017239:Paclitaxel / Q000633:toxicity; D012997:Solvents; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm; D012997:Solvents; D000431:Ethanol; C000515:cremophor EL; D004247:DNA; D017239:Paclitaxel; D005990:Glycerol