Radiorésistance en relation avec l'activation d'oncogène

Abstract

Despite considerable research over the past three decades, the factors that control the response of human tumors to radiation remain poorly understood. Normal human cell strains studied in vitro show a rather narrow range in radiosensitiv ity (1), whereas human tumor cells vary considerably in their sensitivity to the cytotoxic effects of radiation (2,3). Cells from some types of tumors such as soft tissue sarcomas are quite radiosensitive in vitro while a number of cell lines established from various human tumors including squamous cell carcinomas are unusually radioresistant, well beyond the range observed in normal cells (3). The reasons for this variation are not known. Mutations in a number of different oncogenes and tumor suppressor genes have been associated with different types of human cancer. Two observations have suggested a possible role for such genes in the sensitivity of cells to killing by ionizing radiation. First, certain human diploid fibroblast cell strains transformed by the SV-40 virus were found to be less radiosensitive than their non-transformed counterparts. Second, evidence has been presented that transfection of rodent cells with an activated ras oncogene may render these cells more resistant to killing by radiation (4,5). We have studied these two phenomena systematically in normal human diploid fibroblasts, as well as in two human tumor cell lines. Three human diploid cell strains were transfected with an activated Ha-ras oncogene (EJ ras) or the SV-40 T-antigen (6). Multiple clones were isolated from each strain and examined for their sensitivity to x-irradiation in vitro, as well as for morphological alterations, immortalization and tumorigenicity in nude mice. Cells transfected with the activated ras oncogene alone showed no morphological alterations nor significant changes in radiosensitiv ity. Clones expressing SV-40 T-antigen, on the other hand, were significantly radioresistant as compared with their parental cells or clones tranfected with the neo gene only. This radioresistant phenotype persisted in post-crisis, immortalized cell lines. These data suggest that expression of the SV-40 T-antigen but not activated Ha-ras plays a significant role in the radiosensitivity of human diploid cells. The radioresistant phenotype was not related to the enhanced level of genetic instability seen in pre-crisis and newly immortalized cells, nor to the process of immortalizati on itself.