Biegel J A, Conner M K, Boggs S S
Cancer Res. 1982 Jul;42(7):2816-20.
The present studies were designed to evaluate the role of cell cycle time and time of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) administration on the persistence of sister chromatid exchange (SCE)-inducing lesions in normal and lymphoma second- and third-division AKR bone marrow cells. Normal second-division cells harvested from mice given injections of BCNU at the start of an 18-, 24-, or 28-hr 5-bromo-2-deoxyuridine (BrdUrd) infusion exhibited similar linear dose-dependent increases in SCE frequencies (p greater than 0.05). The faster-cycling lymphoma cells, harvested after 18-hr BrdUrd infusion, had significantly higher baseline (p less than 0.05) and BCNU-induced increases (p less than 0.001) in SCE frequencies than did normal cells. Dose-dependent increases in SCE frequencies were demonstrated in third-division normal and lymphoma cells from mice infused with BrdUrd for 24 or 28 hr. Whereas lymphoma cells from mice treated with 3.3 mg BCNU per kg exhibited 31.2 +/- 3.9 (S.E.) SCEs in second-division cells and 4.7 +/- 0.4 reciprocal and 22.9 +/- 2.0 nonreciprocal SCEs in third-division cells, a 5 times higher dose of BCNU was required to induce similar levels of 30.0 +/- 0.8 SCEs in second-division cells and 4.4 +/- 0.6 reciprocal and 22.6 +/- 1.2 nonreciprocal SCEs in third-division normal cells. BCNU dose-dependent increases in SCE frequencies were also observed following injection of BCNU 8 hr after the start of BrdUrd infusion. The unexpectedly higher levels of SCEs for both normal and lymphoma cells by this treatment protocol may be due to SCEs occurring at the same site in successive divisions in BrdUrd. Regardless of the protocol used, lower nonreciprocal SCE frequencies were observed in third-division cells relative to SCE frequencies in second-division cells; a possible consequence of the cytotoxicity of BCNU. Injection of BCNU produced significant changes in the proportions of normal and lymphoma cells completing one, two, and three or more divisions in BrdUrd. Lymphoma cells were consistently more sensitive to the specific type(s) of BCNU-induced damage leading to SCEs and cell death than were normal cells. These studies indicated that differences in SCE response were not due to cell cycle time, time of drug administration, or potential for repair. It is therefore suggested that increased sensitivity of lymphoma versus normal cells may be due to increased cellular uptake of BCNU.
本研究旨在评估细胞周期时间以及1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）给药时间对正常及淋巴瘤第二代和第三代AKR骨髓细胞中姐妹染色单体交换（SCE）诱导损伤持续性的作用。从小鼠体内采集的正常第二代细胞，在18小时、24小时或28小时的5-溴-2-脱氧尿苷（BrdUrd）输注开始时注射BCNU，其SCE频率呈现相似的线性剂量依赖性增加（p大于0.05）。在18小时BrdUrd输注后采集的增殖较快的淋巴瘤细胞，其SCE频率的基线（p小于0.05）和BCNU诱导的增加（p小于0.001）均显著高于正常细胞。在接受24或28小时BrdUrd输注的小鼠的第三代正常及淋巴瘤细胞中，也证实了SCE频率的剂量依赖性增加。每千克体重用3.3毫克BCNU处理的小鼠的淋巴瘤细胞，第二代细胞中SCE为31.2±3.9（标准误），第三代细胞中出现4.7±0.4次相互SCE和22.9±2.0次非相互SCE；而在正常细胞的第二代细胞中诱导出类似水平的30.0±0.8次SCE以及在第三代细胞中诱导出4.4±0.6次相互SCE和22.6±1.2次非相互SCE，则需要5倍剂量的BCNU。在BrdUrd输注开始8小时后注射BCNU，也观察到了BCNU剂量依赖性的SCE频率增加。通过该处理方案，正常细胞和淋巴瘤细胞的SCE水平意外升高，可能是由于在BrdUrd连续分裂过程中同一部位发生了SCE。无论采用何种方案，相对于第二代细胞中的SCE频率，第三代细胞中的非相互SCE频率较低；这可能是BCNU细胞毒性的一个后果。注射BCNU导致了在BrdUrd中完成一次、两次和三次或更多次分裂的正常及淋巴瘤细胞比例发生显著变化。淋巴瘤细胞对BCNU诱导的导致SCE和细胞死亡的特定类型损伤始终比正常细胞更敏感。这些研究表明，SCE反应的差异并非由于细胞周期时间、药物给药时间或修复潜力。因此，有人提出淋巴瘤细胞相对于正常细胞敏感性增加可能是由于BCNU细胞摄取增加所致。
