ENHANCEMENT OF TUMOR RADIORESPONSE OF A MURINE MAMMARY-CARCINOMA BY PACLITAXEL

Paclitaxel is a chemotherapeutic agent with potent microtubule stabili zing activity that arrests cells in G(2)-M. Because G(2) and M are the most radiosensitive phases of the cell cycle, paclitaxel has potentia l as a cell cycle-specific radiosensitizer. In this study, we investig ated the ability of paclitaxel to increase tumor radioresponse in vivo using a murine mammary carcinoma and the dependency of this response on accumulation of tumor cells in mitosis. Mice bearing 8-mm tumors we re treated with paclitaxel (60 mg/kg i.v.), 9, 15, or 21 Gy of single- dose radiation, or with a regimen of both agents in which radiation wa s given 1, 9, or 24 h after paclitaxel. The effect of the treatments w as determined by tumor growth delay. Microscopically, the percentage o f mitotically arrested cells was only 4% 1 h after treatment with pacl itaxel, increased to a maximum value of 30% at 9 h, and decreased to 1 2% 24 h after paclitaxel. Paclitaxel enhanced tumor radioresponse by f actors of 1.21 to 2.49. The degree of enhancement increased with incre ases in both the dose of radiation and the time between paclitaxel adm inistration and radiation delivery. Radiation efficiently destroyed mi totically arrested cells by apoptosis. The greatest enhancement of rad iation response was not at the time of the highest mitotic arrest but at 1 day after paclitaxel treatment, showing that paclitaxel potentiat es tumor radioresponse by mechanisms in addition to blocking the cell cycle in mitosis, possibly by tumor reoxygenation. Thus, these results show that paclitaxel is a potent in vivo radiopotentiating agent and has the potential to be usefully combined with radiotherapy.