CHARACTERIZATION OF RADIATION-INDUCED APOPTOSIS IN THE SMALL-INTESTINE AND ITS BIOLOGICAL IMPLICATIONS

The small intestine with its high cell proliferation, well-accepted hierarchy, high radiation susceptibility and low cancer incidence is a useful model for studying the controls of cell replacement. Apoptosis, which represents part of the overall homeostatic process, occurs spontaneously at the stem cell position in the crypts, and very small doses of radiation elevate the levels of apoptosis rapidly in this region. Other cytotoxic agents also target cells in this region including several mutagenic chemicals. Yet other drugs target cells at higher positions in the crypt indicating that all crypt cells possess the programme for apoptosis, but this is normally suppressed in many of the cells. In contrast, high doses of radiation are required to reproductively sterilize the crypts and, using clonal regeneration techniques, the number of clonogenic cells is dependent on the levels of damage induced (dose), i.e. the more injury that is induced the greater number of cells that are recruited into the clonogenic compartment. All doses of radiation trigger rapid changes in proliferation in the stem cell region which suggests that the detection of the induced cell death (even small levels, such as one apoptotic cell per crypt) is efficient and has rapid consequences, p53 may be involved in this damage recognition and apoptosis initiation. The studies to date suggest that apoptosis plays an important role in this tissue in terms of its homeostasis and its protection against carcinogenesis by removal of potentially carcinogenic damaged cells.