Green M H, Waugh A P, Lowe J E, Harcourt S A, Clingen P H, Cole J, Arlett C F
MRC Cell Mutation Unit, Sussex University, Brighton, UK.
Mutat Res. 1996 Feb 19;350(1):239-46. doi: 10.1016/0027-5107(95)00110-7.
Non-cycling human T-lymphocytes from normal subjects show a 10-fold greater sensitivity than fibroblasts to UV-B (280-315 nm) irradiation from a Westinghouse FS20 lamp, but only a 2.7-fold greater sensitivity to UV-C (254 nm) irradiation. Hypersensitivity is associated with a deficiency 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 excision-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 increased by stimulating the cells into cycle. The addition of deoxyribonucleosides does not further enhance survival of cycling cells and they 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 resistance to DNA damage in the absence of division but they also have reduced deoxyribonucleotide pools, which may limit DNA repair. With UV-B irradiation, the exceptionally low dNTP pools in non-cycling T-lymphocytes cause this second effect to predominate. In contrast, with ionising radiation, which forms highly cytotoxic double-strand breaks, non-cycling human T-lymphocytes are slightly more resistant than fibroblasts. Non-cycling cells such as T-lymphocytes should be especially sensitive to agents which produce a high proportion of read excisable damage, but should show normal resistance to agents which highly toxic lesions. It may be possible by choice of DNA damaging agent and manipulation of cellular deoxyribonucleotide pools, to choose regimes which will selectively kill either cycling or non-cycling cells and to improve the efficacy of standard therapeutic procedures. Conditions favouring selective killing of non-dividing T-lymphocytes but sparing stem cells may be of value in bone marrow transplantation. Conditions favouring selective killing of dividing cancer cells but sparing non-dividing normal tissue may be of value in cancer therapy.
来自正常受试者的非循环人类T淋巴细胞对西屋FS20灯发出的UV-B（280 - 315纳米）辐射的敏感性比成纤维细胞高10倍，但对UV-C（254纳米）辐射的敏感性仅高2.7倍。超敏反应与切除修复断裂的重新连接缺陷有关。非循环T淋巴细胞的脱氧核糖核苷酸池极低。向培养基中添加四种脱氧核苷，每种浓度为10^(-5) M，可显著提高存活率，并减少UV-B或UV-C辐射后与切除相关的链断裂的持续存在（Yew和Johnson（1979年），《生物化学与生物物理学学报》562卷，240 - 241页；Green等人（1994年），《突变研究》，315卷，25 - 32页）。通过刺激细胞进入周期也可提高T淋巴细胞的抗紫外线能力。添加脱氧核苷不会进一步提高循环细胞的存活率，且它们达不到在有脱氧核苷存在时非循环细胞所达到的抗性水平。我们认为有两种相反的作用在起作用。脱离周期的细胞在不进行分裂时对DNA损伤可表现出增强的抗性，但它们的脱氧核糖核苷酸池也减少，这可能会限制DNA修复。对于UV-B辐射，非循环T淋巴细胞中极低的dNTP池使这种第二种作用占主导。相比之下，对于形成高度细胞毒性双链断裂的电离辐射，非循环人类T淋巴细胞比成纤维细胞略具抗性。像T淋巴细胞这样的非循环细胞应该对产生高比例可切除损伤的试剂特别敏感，但对产生高度毒性损伤的试剂应表现出正常抗性。通过选择DNA损伤剂和操纵细胞脱氧核糖核苷酸池，有可能选择能够选择性杀死循环或非循环细胞的方案，并提高标准治疗程序的疗效。有利于选择性杀死非分裂T淋巴细胞但保留干细胞的条件在骨髓移植中可能具有价值。有利于选择性杀死分裂癌细胞但保留非分裂正常组织的条件在癌症治疗中可能具有价值。
