Review: a major component of radiation action: interference with intracellular control of differentiation

If genetic lesions were the sole reason of damage induced by ionizing radiation, an increase in the number of identical chromosome sets (polyploidy) may be expected to have a radioprotective effect. This effect is evident in terminally differentiated tissues when the reduction in remaining life span is used as the criterion. This effect is also evident in cells capable of proliferation if cytoplasmic growth during the period of mitotic delay is restricted and the criterion used is continuation of cell proliferation. Both instances demonstrate that polyploidy, in principle, can exert a radioprotective effect, although the genetic damage induced by a given dose increases in approximate proportion to ploidy. However, in mitotically active cells, without restrictions in cytoplasmic growth, differentiation enhancement dominates the effects of genetic lesions, and polyploidy does not protect. Enhancement of differentiation causes damage by eliminating amplification divisions normally passed through by cell progenies before terminal differentiation, thus reducing the number of differentiated cells produced. From its dependence on excess cytoplasmic growth it is concluded that the phenomenon is caused by the interference of ionizing radiation with a mechanism that provides intracellular signals needed to coordinate molecular interactions involved in the control of cell differentiation. This conclusion corresponds to experiments that suggest that intracellular control of differentiation depends on an increase in the ratio of essential cytoplasmic constituents, probably mitochondrial genomes, per nuclear genome. The action of chemical differentiation enhancing agents is similar and an outline of probable mechanisms is presented. Regarding late radiation damage it is concluded that non-specific genetic lesions can enhance differentiation by permanently prolonging the cell cycle, which causes an increased cytoplasmic growth rate per cycle. In this case polyploidy cannot protect because the induced genetic lesions are proportional to ploidy. Both the duration of mitotic delay, and the extent of genetic lesions increase with chromosome size, thus explaining the correlation between interphase chromosome volume and radio-sensitivity. Lack of substantial radioprotecting effect of polyploidy in neoplastically transformed mammalian cells indicates residual capabilities to cease cell proliferation by mechanisms related to terminal differentiation, thus offering clues to tumour therapy.