Valavanis C, Souliotis V L, Kyrtopoulos S A
Laboratory of Chemical Carcinogenesis, National Hellenic Research Foundation, Athens, Greece.
Carcinogenesis. 1994 Aug;15(8):1681-8. doi: 10.1093/carcin/15.8.1681.
The kinetics of accumulation of the premutagenic DNA adduct O6-methylguanine (O6-meG) in the liver, blood leukocytes, lymph nodes and bone marrow of rats was examined and compared after single or multiple doses of procarbazine, a methylating cytostatic drug employed in the treatment of Hodgkin's lymphoma patients, and methylnitrosourea (MNU), an experimental methylating agent and carcinogen. Maximal O6-meG levels occurred 1-2 h after administration of single doses of procarbazine (10 mg/kg) or MNU (1 mg/kg), thereafter decreasing with half-lives of approximately 20-45 h, depending on the tissue. A relatively uniform tissue distribution was observed with both agents, with the liver generally showing highest adduct levels, followed by the lymph nodes, bone marrow and blood leukocytes which contained broadly similar amounts of O6-meG. During daily, oral administration to rats of procarbazine for 10 days at dose rates of 2.5, 5, 10 or 20 mg/kg/day (treatment analogous to that of the MOOP chemotherapy protocol for Hodgkin's lymphoma) followed by animal death on different days (in each case 24 h after the last treatment), a biphasic mode of O6-meG induction was observed: an initially steep build-up during the first 3-4 days was followed by a transient decline in the rate of accumulation, in turn followed by a second wave of accumulation and then a further slow-down. During the same treatment, liver O6-methylguanine-DNA alkyltransferase (AGT) declined in a dose-related manner. AGT recovery after the end of treatment was slow, taking nearly 20 days after the end of the high-dose treatment to return to control levels, despite the fact that all detectable adducts had been lost from DNA within 3 days after the end of treatment. A similar depletion and slow recovery of AGT in the liver, blood lymphocytes, bone marrow and lymph nodes was observed after treatment with a single dose of 100 mg/kg procarbazine. In contrast to these observations, O6-meG accumulated smoothly during a 10 day administration of MNU (1 or 10 mg/kg/day) to reach a steady-state within 5-6 days, while liver AGT was partially depleted after the high dose and recovered fully within 72 h of cessation of treatment. Similarly, a single dose of MNU (35 mg/kg) resulted in AGT depletion followed by rapid recovery in all four tissues examined. It is concluded that procarbazine (but not MNU) causes a decrease in cellular AGT concentrations by a mechanism additional to suicide repair of O6-meG.(ABSTRACT TRUNCATED AT 400 WORDS)
研究并比较了在给大鼠单次或多次注射甲基苄肼（一种用于治疗霍奇金淋巴瘤患者的甲基化细胞抑制药物）和甲基亚硝基脲（MNU，一种实验性甲基化剂和致癌物）后，前诱变DNA加合物O6-甲基鸟嘌呤（O6-meG）在大鼠肝脏、血白细胞、淋巴结和骨髓中的积累动力学。单次注射甲基苄肼（10 mg/kg）或MNU（1 mg/kg）后1 - 2小时出现最大O6-meG水平，此后根据组织不同，以约20 - 45小时的半衰期下降。两种药物均观察到相对均匀的组织分布，肝脏通常显示最高的加合物水平，其次是淋巴结、骨髓和血白细胞，它们含有的O6-meG量大致相似。在以2.5、5、10或20 mg/kg/天的剂量率给大鼠每日口服甲基苄肼10天（治疗类似于霍奇金淋巴瘤的MOOP化疗方案），然后在不同天数处死动物（每种情况均在最后一次治疗后24小时）时，观察到O6-meG诱导的双相模式：最初在第3 - 4天急剧积累，随后积累速率短暂下降，接着是第二轮积累，然后进一步减缓。在相同治疗期间，肝脏O6-甲基鸟嘌呤-DNA烷基转移酶（AGT）以剂量相关的方式下降。治疗结束后AGT的恢复缓慢，高剂量治疗结束后近20天才能恢复到对照水平，尽管在治疗结束后3天内DNA中所有可检测到的加合物都已消失。用单次剂量100 mg/kg甲基苄肼治疗后，在肝脏、血淋巴细胞、骨髓和淋巴结中观察到类似的AGT消耗和缓慢恢复。与这些观察结果相反，在给大鼠10天内每日注射MNU（1或10 mg/kg/天）期间，O6-meG平稳积累，在5 - 6天内达到稳态，而高剂量后肝脏AGT部分耗尽，在治疗停止后72小时内完全恢复。同样，单次注射MNU（35 mg/kg）导致AGT耗尽，随后在所有四个检测组织中迅速恢复。得出的结论是，甲基苄肼（而非MNU）通过除O6-meG自杀修复之外的机制导致细胞AGT浓度降低。（摘要截断于400字）
