Costa A K, Baker M A, Brown J M, Trudell J R
Department of Anesthesia, Stanford University School of Medicine, California 94305-5117.
Cancer Res. 1989 Feb 15;49(4):925-9.
SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is presently undergoing investigation as an antitumor agent because of its high selective toxicity for hypoxic cells in vitro and in vivo. It has been found to be 15 to 200 times more toxic to hypoxic rodent and human cell lines than their normoxic counterparts. We investigated the toxicity of SR 4233 in primary cultures of hepatocytes under various oxygen tensions, ranging from 1% to 20% oxygen. The 50% lethal dose of SR 4233 was found to be 50 times lower in hepatocyte monolayers at 1% O2 versus 20% O2. Even at 4% O2, a concentration that prevails in the pericentral area of the liver under conditions of normal blood flow, SR 4233 was an order of magnitude more toxic than at 20% O2. All samples were analyzed for metabolites, and metabolism was found to be dependent on both the SR 4233 concentration and the oxygen tension. Formation of the major metabolite SR 4317 occurred to the greatest extent at the lowest oxygen concentration and the highest SR 4233 concentration. Very little metabolism occurred at 10 to 20% O2, which is in agreement with data in Chinese hamster ovary cells under aerobic conditions.
SR 4233（3-氨基-1,2,4-苯并三嗪-1,4-二氧化物）目前正在作为一种抗肿瘤药物进行研究，因为它在体外和体内对缺氧细胞具有高度的选择性毒性。已发现它对缺氧的啮齿动物和人类细胞系的毒性比对正常氧合的细胞系高15至200倍。我们研究了SR 4233在不同氧张力（1%至20%氧气）下对原代培养肝细胞的毒性。发现SR 4233在1%氧气条件下的肝细胞单层中的50%致死剂量比在20%氧气条件下低50倍。即使在4%氧气（正常血流条件下肝脏中央周围区域的普遍浓度）时，SR 4233的毒性也比在20%氧气时高一个数量级。对所有样品进行了代谢物分析，发现代谢既取决于SR 4233的浓度，也取决于氧张力。主要代谢物SR 4317的形成在最低氧浓度和最高SR 4233浓度时最为显著。在10%至20%氧气条件下代谢很少发生，这与中国仓鼠卵巢细胞在有氧条件下的数据一致。
