Rojas A, Denekamp J, Johns H, Kjellen E, Tsang R, Nilsson P, Stratford M R, Dennis M F, Joiner M C
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Radiat Res. 1996 Apr;145(4):419-31.
Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.
腺苷二磷酸核糖基转移酶抑制剂，如烟酰胺、3-氨基苯甲酰胺及其他类似物，在某些体外系统中可抑制辐射诱导的亚致死性和/或潜在致死性损伤的修复。因此，我们测试了烟酰胺对两种啮齿动物正常组织体内修复参数的影响。在皮肤方面，通过确定在空气或碳合氧中存在或不存在烟酰胺（0.5 mg g-1）时的α/β比值，监测对剂量分割（5天内1、2、5或10次X射线分割）的敏感性。使用仅在碳合氧中或与在照射前1小时、照射后立即或照射后8小时给予的烟酰胺联合的5次分割/5天的X射线照射方案，研究照射前和照射后的增敏作用。此外，使用中子补充设计研究了目标皮肤克隆原的潜在X射线存活曲线的斜率变化，该变化由α/β比值的变化反映。通过给予单次X射线剂量并随后给予单次补充剂量的d(4)-Be中子，在2.5至25 Gy的X射线剂量范围内获得了氧气±烟酰胺的潜在存活曲线。最后，在小鼠肾脏中，通过使用两个6 Gy分割的分次剂量设计（间隔时间从0到48小时不等，随后是来自中子束的两次补充剂量）来确定X射线损伤随时间的消失情况，从而获得恢复半衰期（t1/2）。单独使用烟酰胺时未观察到表皮损伤的α/β增加，尽管在照射前1小时给予该药物时观察到了增敏作用，但未检测到照射后的增敏作用。在肾脏中，给予或不给予烟酰胺的治疗之间，可修复损伤的总量比例或恢复半衰期均无显著差异。因此，在临床放射治疗中使用烟酰胺时，不应观察到正常组织耐受性降低，这既不是由于剂量分割时的 sparing 减少，也不是由于缩短分次间隔时残留损伤增加所致。最后，除非体内正常组织的辐射损伤修复与肿瘤的修复有显著差异，否则在每次分割1.5至2 Gy、使用碳合氧和烟酰胺的情况下，在啮齿动物肿瘤中看到的大的增敏作用不太可能归因于烟酰胺作为修复抑制剂的作用。
