Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS

Successful radiosensitization requires that tumor cells become more radiose nsitive without causing an equivalent reduction in the survival of cells of the surrounding normal tissues. Since tumor cell radiosensitivity can be i nfluenced by RAS oncogene activation, we have hypothesized that inhibition of oncogenic RAS activity would lead to radiosensitization of tumors with a ctivated RAS. We previously showed in tissue culture that prenyltransferase treatment of cells with activated RAS resulted in radiosensitization, wher eas treatment of cells with wild-type RAS had no effect on radiation surviv al. Here we ask whether the findings obtained in vitro have applicability i n vivo. We found that treatment of nude mice bearing T24 tumor cell xenogra fts with farnesyltransferase inhibitors resulted in a significant and syner gistic reduction in tumor cell survival after irradiation. The regrowth of T24 tumors expressing activated RAS was also significantly prolonged by the addition of treatment with farnesyltransferase inhibitors compared to the regrowth after irradiation alone. In contrast, there was no effect on the r adiosensitivity of HT-29 tumors expressing wild-type RAS. These results dem onstrate that specific radiosensitization of tumors expressing activated RA S oncogenes can be obtained in vivo. (C) 2000 by Radiation Research Society .