[Very low-dose hyper-radiosensitivity: impact for radiotherapy of micrometastases]

Radiobiologists have pointed out a novel radiobiological phenomenon observed in many tumor and normal cell lines: hyper-radiosensitivity to very low-dose (HRS) followed by induced radioresistance (IRR) after a threshold dose of 0.1-0.3 Gy that depends on the cell line. Radioresistance at high dose (i.e. higher than 0.5 Gy) and metastatic potential of tumor cells are likely major factors of failure in radiotherapy. A careful review of literature suggests that: 1) radiotherapy does not increase the metastatic potential of tumor cells; 2) radioresistance at high dose and metastatic potential are not related. However, inside a given tumor cell line, highly metastatic clones may elicit more cells showing HRS or are more radiosensitive at high dose than poorly metastatic ones. Recent data obtained from molecular techniques (comet and immunofluorescence assays) applied to single cells irradiated at very low radiation doses (1-100 mGy) suggest that DNA single-strand breaks (SSB) and double-strand breaks (DSB) may be the key-lesions responsible for the HRS phenomenon. These data suggest that the HRS phenomenon may find application in radiotherapy for micrometastasis. These early disseminated and probably unvascularised cells may escape the influence of high-dose chemotherapy after excision of the primary tumor. Considering the link between metastatic potential and HRS, we have previously proposed to apply very low-dose total body irradiation (TBI) at M(0) stage that may prevent the development of micrometastases. Literature data suggest that the smallest radiation dose that can produce HRS without increasing the risk of cancer may be in the milliGrays range.