Taylor Y C, Brown J M
Department of Therapeutic Radiology, Stanford University School of Medicine, California 94305.
Radiat Res. 1987 Oct;112(1):134-45.
The objective of this study was to characterize the extent of and mechanisms involved in radiosensitization by 2-nitroimidazoles in multifraction schedules using low doses per fraction. For this purpose, contact-inhibited monolayers of C3H 10T1/2 cells were given 1.7 Gy every 12 h and plated 12 h after the last dose received to allow full repair of potentially lethal damage (PLD). Severe hypoxia was obtained by a 1-h gassing procedure at room temperature immediately before each irradiation. No toxicity occurred as a consequence of multiple exposures to 5 mM misonidazole (MISO) or SR 2508 (2508) during the deoxygenation procedure. Experimental conditions during the pregassing and irradiation (presence of drug and gas mixture) were appropriately manipulated to test for the different mechanisms of radiosensitization demonstrated by nitroimidazoles. A very low oxygen enhancement ratio (OER) results under these conditions (1.34). Exposure to 5 mM MISO or 2508 during the deoxygenation and irradiation of hypoxic cells resulted in greater radiosensitization than could be accounted for by oxygen-mimetic sensitization alone (MISO and 2508 enhancement ratios were greater than the OER). Pregassing cells with N2 in the presence of 5 mM drug sensitized cells which were subsequently irradiated under aerobic conditions (drug free), indicating the occurrence of the "preincubation effect" (which does not require hypoxia or the drug's presence during the irradiation). Thus, for the hypoxic irradiations, the preincubation effect could account for the greater sensitization by nitroimidazoles than by oxygen. The presence of 5 mM drug only during the irradiation of aerobic cells produced radiosensitization in both multifraction and single-dose experiments with delayed plating. This sensitization has been previously shown to involve reduced PLD repair. Finally, maximum radiosensitization occurred in the multifraction schedule when a transient period of hypoxia with drug preceded an aerobic irradiation with drug present, thus combining the benefits of both the preincubation effect and PLD repair inhibition. This work demonstrates the possibility that effects other than oxygen-mimetic radiosensitization could be largely responsible for the sensitization seen in multifraction schedules, particularly when the OER is already low and only transient periods of hypoxia occur.
本研究的目的是确定在使用低分割剂量方案时，2-硝基咪唑在多分割放疗中放射增敏的程度及相关机制。为此，将接触抑制的C3H 10T1/2细胞单层每12小时给予1.7 Gy照射，并在接受最后一剂照射后12小时接种，以使潜在致死性损伤（PLD）完全修复。在每次照射前立即在室温下通过1小时的通气程序诱导严重缺氧。在脱氧过程中多次暴露于5 mM米索硝唑（MISO）或SR 2508（2508）未产生毒性。在预通气和照射期间（药物和气体混合物的存在）对实验条件进行适当控制，以测试硝基咪唑所显示的不同放射增敏机制。在这些条件下产生了非常低的氧增强比（OER）（1.34）。在缺氧细胞的脱氧和照射过程中暴露于5 mM MISO或2508导致的放射增敏作用比仅由氧模拟增敏作用所能解释的更大（MISO和2508的增强比大于OER）。在5 mM药物存在下用N2对细胞进行预通气，使随后在有氧条件下（无药物）照射的细胞致敏，表明发生了“预孵育效应”（在照射期间不需要缺氧或药物存在）。因此，对于缺氧照射，预孵育效应可以解释硝基咪唑比氧具有更大的增敏作用。仅在有氧细胞照射期间存在5 mM药物，在多分割和延迟接种的单剂量实验中均产生了放射增敏作用。先前已表明这种增敏作用涉及PLD修复减少。最后，当在有氧照射且存在药物之前有一段短暂的缺氧与药物同时存在的时期时，在多分割方案中出现了最大程度的放射增敏，从而结合了预孵育效应和PLD修复抑制的益处。这项工作表明，除氧模拟放射增敏作用之外的其他效应可能在很大程度上导致了在多分割方案中观察到的增敏作用，特别是当OER已经很低且仅出现短暂的缺氧时期时。
