Apoptosis and mitotic cell death: their relative contributions to normal-tissue and tumour radiation response.

The target-cell theory of tissue responses is reviewed with reference to the radiosensitivity of proposed target cells in bone marrow, intestine, epidermis, and spermatogenesis. The difficulties in precisely identifying target cells using histological/cell marker criteria, and hence determining the role of their mode of death in tissue responses, are being circumvented to some extent by the recent use of mice deficient in gene products required for radiation-induced apoptosis. In this case cell death results from 'mitotic cell death' and e.g. in the case of p53, any remaining p53-independent apoptosis. In the p53 null mouse, cell survival levels are increased in bone marrow and intestine but decreased in the testis. Different interpretations, based on the lack of p53-dependent apoptosis or the lack of a permanently induced G1-arrest in the case of marrow fibroblasts, can be applied to the results for different cell types. Hence both apoptosis and mitotic cell death can variously be involved as contributing to target-cell sensitivity and hence to early reactions in these tissues after irradiation. It is still unclear whether, or how, the mode of cell death (apoptotic versus mitotic) determines the radiosensitivity and response of tumours. In experimental tumours, the levels of radiation-induced apoptosis have been shown to correlate both with the in vivo response to radiation and the degree of spontaneous apoptosis in the tumours. Measurements of spontaneous apoptosis in human tumours, however, have yielded conflicting data with high apoptotic levels significantly correlating with both good and poor prognosis in different studies. There is one report of a lack of relationship between intrinsic radiosensitivity and spontaneous apoptosis in cervical cancers. In contrast several studies have reported correlations between apoptosis levels and the degree of tumour cell proliferation. Tumour hypoxia has also been shown to increase apoptosis. These data suggest that tumour apoptosis may be a reflection of intrinsic radiosensitivity, tumour cell proliferation and tumour hypoxia. Its relative importance will probably be tumour type, size and stage related.