Cohen J D, Schmitt C L, Robins H I
Department of Neurological Surgery, University of Wisconsin Clinical Sciences Center, Madison 53792.
Radiat Res. 1991 Jun;126(3):372-8.
This study tested whether thymidine, a naturally occurring nucleoside metabolite, could increase the sensitivity of human T-cell neoplasms to ionizing irradiation and whether adding 41.8 degrees C hyperthermia (X 1 h) to the combination of thymidine and irradiation would further enhance killing of cells by radiation. The magnitude of cytotoxicity induced directly by thymidine was also evaluated. Finally, the ability of 2'-deoxycytidine to prevent thymidine-induced cytotoxicity and radiosensitization was studied. Using JM and MOLT3, two human T-cell acute lymphoblastic leukemias, it was found that thymidine itself was cytotoxic and the toxicity appeared rapidly upon exposure to the drug (i.e., at 4 h). Thymidine caused significant radiosensitization, and thymidine plus 1 h of 41.8 degrees C hyperthermia enhanced radiation-induced killing significantly more than did thymidine or hyperthermia separately. The addition of 2'-deoxycytidine only partly reversed thymidine-induced killing and did not prevent thymidine-induced radiosensitization. The applicability of these results to the clinical management of T- and null-cell malignancies is discussed, as is the presumed mechanistic basis for these observations relative to deoxyribonucleoside metabolism, NAD metabolism, and inhibition of poly(ADP-ribose) polymerase.
本研究检测了天然存在的核苷代谢物胸苷是否能增加人T细胞肿瘤对电离辐射的敏感性，以及在胸苷与辐射联合应用时加入41.8℃热疗（1小时）是否会进一步增强辐射对细胞的杀伤作用。还评估了胸苷直接诱导的细胞毒性程度。最后，研究了2'-脱氧胞苷预防胸苷诱导的细胞毒性和放射增敏作用的能力。使用两种人T细胞急性淋巴细胞白血病JM和MOLT3，发现胸苷本身具有细胞毒性，且在接触该药物后（即4小时时）毒性迅速出现。胸苷引起显著的放射增敏作用，并且胸苷加1小时41.8℃热疗比单独使用胸苷或热疗更显著地增强了辐射诱导的杀伤作用。加入2'-脱氧胞苷仅部分逆转了胸苷诱导的杀伤作用，且未预防胸苷诱导的放射增敏作用。讨论了这些结果在T细胞和裸细胞恶性肿瘤临床管理中的适用性，以及相对于脱氧核糖核苷代谢、NAD代谢和聚（ADP-核糖）聚合酶抑制作用而言这些观察结果的推测机制基础。
