Cytotoxicity of fractionated paclitaxel (Taxol) administration in vitro

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.

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.

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.

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.