Zeman E M, Lemmon M J, Brown J M
Department of Radiation Oncology, Stanford University Medical Center, CA 94305.
Int J Radiat Oncol Biol Phys. 1990 Jan;18(1):125-32. doi: 10.1016/0360-3016(90)90276-p.
During the past 3 years, our laboratory has identified and characterized the drug SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) as the lead compound in a series of benzotriazine di-N-oxides that are both potent and selective killers of hypoxic cells in vitro and in rodent tumors in vivo. Recently, we have identified a novel property of SR 4233: the ability of a pre- or post-irradiation drug treatment under hypoxic conditions to radiosensitize aerobic cells in culture. For the mouse cell lines RIF-1 and SCC VII in vitro, this radiosensitization took the form of a steepening of the slope of the acute dose radiation survival curve, although there was also reduced survival in the "shoulder region" of the curve. For both cell lines, the sensitization occurred whether the hypoxic drug exposure was given immediately before or after the irradiation under aerobic conditions. To determine whether radiosensitization could be demonstrated for RIF-1 and SCC VII mouse tumors in vivo, tumor-bearing animals were exposed to 4 daily dose fractions of 5 Gy of X rays either alone, or followed immediately by injections of SR 4233 and the vasoactive agent hydralazine, which increases tumor hypoxia and therefore can potentiate the effect of such hypoxiaspecific drugs. Although treatment with the SR 4233/hydralazine combination after each dose fraction reduced tumor cell survival to between 10(-5) and 10(-6), near the limits of resolution of the clonogenic survival assay, the effect appeared to be strictly additive, suggesting that with this fractionated protocol, aerobic radiosensitization could not be detected. This is likely to be a consequence of the exquisite direct cytotoxicity of the SR 4233 and hydralazine combination toward the hypoxic cells in tumors.
在过去3年中，我们实验室已鉴定并表征了药物SR 4233（3-氨基-1,2,4-苯并三嗪1,4-二氧化物），它是一系列苯并三嗪二-N-氧化物中的先导化合物，这些化合物在体外对缺氧细胞以及在体内对啮齿动物肿瘤都是强效且选择性的杀手。最近，我们发现了SR 4233的一种新特性：在缺氧条件下，照射前或照射后进行药物处理能够使培养中的需氧细胞产生放射增敏作用。对于体外培养的小鼠细胞系RIF-1和SCC VII，这种放射增敏表现为急性剂量辐射存活曲线的斜率变陡，尽管曲线“肩部区域”的存活率也有所降低。对于这两种细胞系，无论缺氧药物暴露是在需氧条件下照射之前还是之后立即进行，都会发生增敏作用。为了确定体内的RIF-1和SCC VII小鼠肿瘤是否能表现出放射增敏作用，将荷瘤动物单独给予每日4次、每次5 Gy的X射线剂量，或者在每次照射后立即注射SR 4233和血管活性药物肼屈嗪，后者会增加肿瘤缺氧程度，因此可增强这类缺氧特异性药物的效果。尽管每次剂量照射后用SR 4233/肼屈嗪联合处理可将肿瘤细胞存活率降低至10^(-5)到10^(-6)之间，接近克隆形成存活测定的分辨率极限，但这种作用似乎只是严格的相加作用，这表明采用这种分次给药方案无法检测到需氧放射增敏作用。这可能是由于SR 4233和肼屈嗪联合对肿瘤中的缺氧细胞具有极强的直接细胞毒性所致。
