Gerner E W, Tome M E, Fry S E, Bowden G T
Department of Radiation Oncology, University of Arizona Health Sciences Center, Tucson 85724.
Cancer Res. 1988 Sep 1;48(17):4881-5.
Polyamines are involved in many cellular processes, including DNA structure and function. Since DNA, or some DNA-containing structure, is known to be the target for cell killing induced by ionizing radiation and a number of chemotherapeutic agents, we investigated the effects of polyamine depletion on cytotoxic responses of Chinese hamster cells to X-irradiation. Colony forming ability after single, acute radiation exposures of cells growing under oxic conditions was minimally affected by endogenous putrescine and spermidine depletion, achieved after treatment with alpha-difluoromethylornithine. Survival of cells rendered hypoxic and then irradiated was unaffected by alpha-difluoromethylornithine treatment. However, cellular recovery processes were nearly completely suppressed in polyamine-depleted cells, including sublethal damage recovery, as evidenced by split-dose irradiations in log phase cultures, and potentially lethal damage recovery, observed when growth-inhibited cultures were allowed time to repair radiation damage prior to being plated for colony formation. Both these recovery processes were restored by exogenous putrescine treatment. Reaccumulation of intracellular spermidine content closely correlated with restoration of potentially lethal damage recovery. Depletion of putrescine and spermidine pools had little effect on either single or double strand DNA break production or rejoining. These data demonstrate that both sublethal and potentially lethal damage recovery are polyamine-dependent processes in Chinese hamster cells, and imply that the mechanisms by which hamster cells recovery from these types of radiation damage are unrelated to their ability to rejoin DNA strand breaks, at least during the first hour after irradiation. Finally, these results suggest that the depletion of tumor polyamine content may be an effective method of enhancing the sensitivity of human tumors to fractionated radiotherapy.
多胺参与许多细胞过程，包括DNA的结构和功能。由于DNA或某些含DNA的结构是电离辐射和多种化疗药物诱导细胞杀伤的靶点，我们研究了多胺耗竭对中国仓鼠细胞对X射线照射的细胞毒性反应的影响。在有氧条件下生长的细胞单次急性辐射暴露后的集落形成能力，受α-二氟甲基鸟氨酸处理后内源性腐胺和亚精胺耗竭的影响最小。使细胞缺氧然后照射，其存活不受α-二氟甲基鸟氨酸处理的影响。然而，多胺耗竭的细胞中细胞恢复过程几乎被完全抑制，包括亚致死损伤恢复（对数期培养物中的分次剂量照射证明）和潜在致死损伤恢复（当生长受抑制的培养物在接种形成集落之前有时间修复辐射损伤时观察到）。这两种恢复过程都通过外源性腐胺处理得以恢复。细胞内亚精胺含量的重新积累与潜在致死损伤恢复的恢复密切相关。腐胺和亚精胺库的耗竭对单链或双链DNA断裂的产生或重新连接几乎没有影响。这些数据表明，亚致死损伤和潜在致死损伤恢复在中国仓鼠细胞中都是多胺依赖性过程，这意味着仓鼠细胞从这些类型的辐射损伤中恢复的机制与其重新连接DNA链断裂的能力无关，至少在照射后的第一小时内是这样。最后，这些结果表明，降低肿瘤多胺含量可能是提高人类肿瘤对分次放疗敏感性的有效方法。
