SR 4233在具备DNA修复能力和缺乏DNA修复能力的细胞培养物中的细胞毒性及代谢情况。
SR 4233 cytotoxicity and metabolism in DNA repair-competent and repair-deficient cell cultures.
作者信息
Biedermann K A, Wang J, Graham R P, Brown J M
机构信息
Department of Radiation Oncology, Stanford University School of Medicine, California 94305.
出版信息
Br J Cancer. 1991 Mar;63(3):358-62. doi: 10.1038/bjc.1991.85.
In order to understand in more detail the mechanism underlying the preferential hypoxic cytotoxicity of the benzotriazine N-oxide SR 4233, we have compared the hypoxic cytotoxicity of this drug to the rates of hypoxic metabolism in both DNA double strand break repair-competent and repair-deficient cell cultures. Rodent SCCVII cells and repair deficient, radiation sensitive cells (rodent XR-1, V-3, and human AT5BI) were most sensitive to SR 4233 under hypoxia with a lethal dose needed to kill 50% of cells (LD50) of less than 5 microM. SR 4233 was less cytotoxic to human AG 1522 (LD50 = 18 microM), CHO 4364 (LD50 = 25 microM) and human HT 1080 cells (LD50 = 33 microM). The sensitivities to SR 4233 were found to be inversely proportional to the rates of SR 4233 metabolism in repair-competent cells (R2 = 0.9). However, XR-1 and V-3 cells were more sensitive to SR 4233 than predicted by the metabolism rate. Thus, the toxicity by SR 4233 towards hypoxic cells appears to result from two mechanisms; the rate of drug metabolism and the ability to repair DNA double strand breaks.
为了更详细地了解苯并三嗪氮氧化物SR 4233优先产生缺氧细胞毒性的潜在机制，我们比较了该药物在DNA双链断裂修复能力正常和修复缺陷的细胞培养物中的缺氧细胞毒性与缺氧代谢率。啮齿动物SCCVII细胞以及修复缺陷、对辐射敏感的细胞（啮齿动物XR-1、V-3和人类AT5BI）在缺氧条件下对SR 4233最为敏感，杀死50%细胞所需的致死剂量（LD50）小于5微摩尔。SR 4233对人类AG 1522（LD50 = 18微摩尔）、CHO 4364（LD50 = 25微摩尔）和人类HT 1080细胞（LD50 = 33微摩尔）的细胞毒性较小。发现对SR 4233的敏感性与修复能力正常的细胞中SR 4233的代谢率成反比（R2 = 0.9）。然而，XR-1和V-3细胞对SR 4233的敏感性比根据代谢率预测的更高。因此，SR 4233对缺氧细胞的毒性似乎源于两种机制；药物代谢率和修复DNA双链断裂的能力。
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