Taxol and ionizing radiation: interaction and mechanisms.

Abstract

Taxol has been shown to be clinically active against several types of human tumors. To assess the potential oncogenic effect of taxol, the in vitro cytotoxic and oncogenic transforming effects of taxol, either alone or in combination with gamma-irradiation, were examined. Exponentially growing mouse C3H 10T1/2 cells were treated with taxol with or without concurrent gamma-irradiation. After treatment, cultures were replated for both clonogenic survival and transformation assays. To determine the effects of taxol on cell cycle kinetics, treated cells were concurrently labelled with bromodeoxyuridine coupled with fluorescein. Accumulated mitotic cells were isolated by the shake-off technique and their plating efficiency and radiosensitivity were determined. Taxol induced a dose dependent toxicity in 10T1/2 cells. In contrast to human tumor cells in culture, the mitotic block induced by a 100 nM dose of taxol in 10T1/2 cells was only partial. While taxol was ineffective in transformant induction, it enhanced the oncogenic transforming potential of gamma-rays in a supra-additive manner. The fact that approximately 15% of taxol-induced mitotic cells were clonogenically viable and at a cell cycle stage that was most radiosensitive suggests a mechanistic basis for the observed enhancement in transformation incidence by ionizing radiation. Taxol enhances the oncogenicity of radiation by partially blocking the 10T1/2 cells in G2/M phases of the cell cycle, phases that are most sensitive to radiation induced oncogenic transformation.