Cytotoxicity of fractionated paclitaxel (Taxol) administration in vitro.

PURPOSE

Paclitaxel (Taxol) is a new anticancer agent with a novel mechanism of action. It has demonstrated broad clinical activity in a variety of malignancies. Several aspects of paclitaxel's usage remain to be clarified, including the optimal treatment schedule. Furthermore, the diluent of paclitaxel, Cremophor EL/ethanol, alone has shown to be markedly active in tumor samples.

MATERIAL AND METHODS

The in-vitro cytotoxicity of paclitaxel (Taxol) due to single dose (1 x 10 microM/day, day 1 incubation time: 3 h and 15 h) and fractionated exposure (5 x 2 microM/day, day 1 to 5 incubation time: 3 h/day) was evaluated, measuring surviving fraction (clonogenic assay) and DNA distribution (flow cytometric analysis). In the control population, the diluent Cremophor EL/ethanol or a phosphate buffered salt solution (PBS) were applied using identical doses and schedules. A mammalian fibroblast cell line (HyB14FAF28) was used.

RESULTS

Fractionated application of paclitaxel (Taxol) produced a significant lower clonogenic survival (0.63) in comparison with single dose exposure for 3 h (0.84) and 15 h (0.82). DNA analysis showed no evidence for a significant difference in DNA distribution of the paclitaxel-specific G2/M phase over a 10-day period. Controls with the diluent Cremophor EL/ethanol showed a clonogenic survival of 0.87 (3 h exposure) and 0.88 (15 h exposure) versus 0.65 after fractionated drug administration (5 x 2 microM/day, day 1 to 5, incubation time: 3 h/day). PBS controls and untreated controls did not show any significant effect.

CONCLUSIONS

It seems that clonogenic survival after Taxol exposure of this mammalian fibroblast cell line varies with treatment schedule through a yet unknown process that does not involve G2/M arrest. The results indicate the treatment effects to be mainly based on the diluent combination without any further benefit induced by paclitaxel.