In the interest of improving cancer treatment, considerable attention has been placed on modification of radiation damage, particularly toward enhancement. A variety of chemotherapy agents have demonstrated radiation sensitization; however, recently we have focused attention on the relatively new agent paclitaxel (Taxol[R]). A series of in vitro studies evaluating paclitaxel as a radiation sensitizer has recently been completed. Paclitaxel blocks cells in G2/M phases of the cell cycle. It has been known for decades that cells in late G2 or M are more sensitive to radiation than cells in other phases of the cell cycle. We have shown that the human breast adenocarcinoma cell line MCF7 is sensitized to radiation by paclitaxel with a radiation enhancement ratio (RER) of 1.9. Radiation sensitization by paclitaxel in other human tumor cell lines was found to be variable (RER ranged from 1.0 to 1.5). Based on our in vitro data, breast cancer should be most suitable for combined radiation and paclitaxel. Interestingly, human lung adenocarcinoma cells were not radiosensitized by paclitaxel despite the induction of a pronounced cell cycle block in G2/M. The reason for this finding is being actively studied. As a major new initiative, we plan to conduct in vivo studies of human breast cancer in xenograft model. We propose to implant mice with MCF7 tumors and examine the schedule and dose dependence of paclitaxel as a radiation sensitizer. We believe these studies will be critical for a thorough comprehension of the appropriate clinical use of paclitaxel and radiation. To date, there are no in vivo data on the use of paclitaxel with radiation. Our proposed studies will fill this void in our understanding of how to introduce paclitaxel into a multimodality treatment program for breast cancer. Another radiation sensitizer we continue to study is the halogenated pyrimidine iododeoxyuridine (IdUrd). Recent studies have shown that maximum incorporation of IdUrd is achieved in one week of drug infusion instead of two in patients with new head and neck tumors receiving continuous infusion IdUrd. This finding will lead to a new protocol of whether administration of IdUrd over 1 week will 1) reduce toxicity and 2) provide radiosensitization. Preclinical studies combining IdUrd/paclitaxel/radiation are planned.
