Zeman E M, Brown J M
Department of Radiation Oncology, Stanford University Medical Center, CA 94305.
Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):967-71. doi: 10.1016/0360-3016(89)90897-3.
SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent which exhibits highly selective killing of hypoxic cells in a variety of mammalian cell lines in vitro and in murine tumors in vivo. The selective toxicity of the drug results from its one-electron reduction under hypoxic conditions to form a free radical intermediate capable of damaging DNA, through the formation of strand breaks. Using the neutral filter elution assay, SR 4233 was found to be more efficient at producing DNA double strand breaks in Chinese hamster ovary (CHO) cells than an equitoxic dose of gamma-rays. Drug and radiation sequencing experiments were also performed, with both cell survival and DNA strand break rejoining used as endpoints. As a result of these studies, we now describe two additional properties of SR 4233: (a) radiosensitization of aerobic cells in culture produced by hypoxic incubation with drug either before or after irradiation, and (b) the inhibition of subsequent rejoining of radiation-induced DNA double strand breaks after hypoxic pretreatment with drug. The magnitude of the radiosensitization produced did not vary for drug treatments which, when given alone, reduced cell survival over a range from 30% to 2%. The extent of DNA repair inhibition increased with increasing severity of the SR 4233 pretreatment, but was quite small for non-lethal drug exposures.
SR 4233（3-氨基-1,2,4-苯并三嗪1,4-二氧化物）是一种生物还原剂，在体外多种哺乳动物细胞系以及体内小鼠肿瘤中，它对缺氧细胞具有高度选择性杀伤作用。该药物的选择性毒性源于其在缺氧条件下通过单电子还原形成一种能够通过形成链断裂来损伤DNA的自由基中间体。使用中性滤膜洗脱试验发现，与等毒性剂量的γ射线相比，SR 4233在产生中国仓鼠卵巢（CHO）细胞DNA双链断裂方面更有效。还进行了药物与辐射顺序实验，以细胞存活和DNA链断裂重接作为终点指标。这些研究结果使我们现在描述SR 4233的另外两个特性：（a）在照射前或照射后用药物进行缺氧孵育可使培养中的需氧细胞产生放射增敏作用，以及（b）在用药物进行缺氧预处理后可抑制辐射诱导的DNA双链断裂的后续重接。单独给予药物时，在30%至2%的范围内降低细胞存活的药物处理所产生的放射增敏程度没有变化。随着SR 4233预处理严重程度的增加，DNA修复抑制程度增加，但对于非致死性药物暴露来说，这种抑制程度相当小。
