Background: Docetaxel (Taxotere) has gained increasing attention in clinical applications. We investigated the cytotoxic and radiosensitizing potential of docetaxel at nanomolar concentrations in six cell lines derived from tumors that rarely respond to radiation or chemotherapy, with special consideration of mechanisms of resistance, including the p53 mutational status.
Methods: Cells derived from carcinomas of the human stomach (p53 mutant Hs746T, p53 wild type AGS), cervix (p53 wild type CaSki, p53 mutant HeLa) or pancreas (p53 mutant BxPC3 and Capan-1) were treated for 24 h with docetaxel at various concentrations (0.1-5 nM) to obtain drug doses for inhibiting clonogenicity by approximately 50% (IC(50)). Cells were X-irradiated without docetaxel or after 24 h of docetaxel treatment at IC(50). Radiation doses ranged from 0 up to 10 Gy. Mitotic index, multinucleation, apoptosis and necrosis after 24 h of drug exposure at 1 nM were quantified in representative gastric and cervical cell lines by fluorescence microscopy.
Results: Docetaxel treatment for 24 h resulted in a dose-dependent loss of clonogenicity, with 1.0 or 0.3 nM producing approximately 50% survival of gastric or cervix and pancreatic cells, respectively. After correction for the drug toxicity, the combination of isoeffective concentrations of docetaxel with graded X-ray doses resulted either in a moderate synergy or additivity. The dose reduction factors at the 50 and 20% survival levels were statistically greater than those for Hs746T or AGS cells. For CaSki, HeLa, BxPC3 or Capan-1 cells, the dose reduction factors were statistically not different from unity.
Conclusion: Docetaxel was active against tumor cells of different origins. Combined effects of docetaxel and radiation were at least additive and depended on the intrinsic sensitivity to drug alone. There was no significant evidence of drug-induced mitotic arrest. Compared to drug-resistant gastric cells, exposure to the drug alone of drug-sensitive cervical cells resulted in more severe multinucleation. The p53 status did not contribute directly to the effect of drug alone or in combination with radiation.