CHEMICAL MODIFICATION OF THE RADIATION RESPONSE

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In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage, particularly toward enhancement. A variety of chemotherapy agents have demonstrated radiation sensitization and for the past few years we have focused attention on the relatively new agent paclitaxel (Taxol). We have shown that paclitaxel treatment induces a block in G2/M of the cell cycle) and radiosensitizes a number of human tumor cell lines. Of particular note was the radiosensitization of a human breast adenocarcinoma cell line MCF7. Paclitaxel treatment combined with radiation resulted in a radiation enhancement ratio (RER) of 1.9. Based on our in vitro data, breast cancer should be most suitable for combined radiation and paclitaxel. We were initially puzzled that 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 resides in the differential exit times in S phase (a radioresistant portion of the cell cycle) among cell types. While not related to radiation, we have conducted preliminary pre-clinical studies which show that paclitaxel may be suitably combined with hyperthermia (an experimental cancer treatment modality) as long as the paclitaxel treatment precedes the hyperthermia treatment. This information will be extremely useful to clinicians designing human clinical trials combining paclitaxel and hyperthermia. We have also initiated studies evaluating gemcitabine, quinocarmycin, and 9-amino camptothecin as radiation sensitizers. Preliminary studies show that gemcitabine and 9-amino camptothecin enhance radiation sensitivity (enhancement ratios ranging from 1.3-1.5) of human pancreas and lung cancer cell lines. Other chemotherapy agents to be evaluated as radiation sensitizers include flavopiridol, rebeccamycin, and rhizoxin.