PROTECTIVE EFFECT OF DEOXYRIBONUCLEOSIDES ON UV-IRRADIATED HUMAN PERIPHERAL-BLOOD T-LYMPHOCYTES - POSSIBILITIES FOR THE SELECTIVE KILLING OF EITHER CYCLING OR NON-CYCLING CELLS

Non-cycling human T-lymphocytes from normal subjects show a 10-fold gr eater sensitivity than fibroblasts to UV-B (280-315 nm) irradiation fr om a Westinghouse FS20 lamp, but only a 2.7-fold greater sensitivity t o UV-C (254 nm) irradiation. Hypersensitivity is associated with a def iciency in the rejoining of excision breaks. Non-cycling T-lymphocytes have extremely low deoxyribonucleotide pools. Addition to the medium of the four deoxyribonucleosides, each at a concentration of 10(-5) M, substantially increases survival and reduces the persistence of excis ion-related strand breaks following UV-B or UV-C irradiation (Yew and Johnson (1979) Biochim. Biophys. Acta 562, 240-241; Green et al. (1994 ) Mutation Res., 315, 25-32). UV-resistance of T-lymphocytes is also i ncreased by stimulating the cells into cycle. The addition of deoxyrib onucleosides does not further enhance survival of cycling cells and th ey do not reach the level of resistance achieved by non-cycling cells in the presence of deoxyribonucleosides. We suggest that two opposing effects are in operation. Cells out of cycle can show increased resist ance to DNA damage in the absence of division but they also have reduc ed deoxyribonucleotide pools, which may limit DNA repair. With UV-B ir radiation, the exceptionally low dNTP pools in non-cycling T-lymphocyt es cause this second effect to predominate. In contrast, with ionising radiation, which forms highly cytotoxic double-strand breaks, non-cyc ling human T-lymphocytes are slightly more resistant than fibroblasts. Non-cycling cells such as T-lymphocytes should be especially sensitiv e to agents which produce a high proportion of readily excisable damag e, but should show normal resistance to agents which produce highly to xic lesions. It may be possible by choice of DNA damaging agent and ma nipulation of cellular deoxyribonucleotide pools, to choose regimes wh ich will selectively kill either cycling or non-cycling cells and to i mprove the efficacy of standard therapeutic procedures. Conditions fav ouring selective killing of non-dividing T-lymphocytes but sparing ste m cells may be of value in bone marrow transplantation. Conditions fav ouring selective killing of dividing cancer cells but sparing non-divi ding normal tissue may be of value in cancer therapy.