Langmuir V K, Mendonca H L
Laboratory of Cell and Molecular Biology, SRI International, Menlo Park, California 94025.
Radiat Res. 1992 Dec;132(3):351-8.
Radioimmunotherapy is hindered by the slow penetration of antibody molecules into tumors. Cells that are poorly targeted by antibody, because of their distance from feeding blood vessels, receive the lowest radiation dose, and this problem is compounded if there are radioresistant hypoxic cells present. It would be desirable to combine radioimmunotherapy with an agent that is preferentially toxic to these cells. SR 4233 is a potent hypoxic cytotoxin, and it was combined with 131I-NR-LU-10 to treat LS174T human colon adenocarcinoma multicell spheroids and nude mouse xenografts for these studies. Under conditions of severe hypoxia (< 0.01% O2), 2 h of pretreatment or 18 h of simultaneous treatment with SR 4233 did not significantly enhance the effectiveness of 131I-NR-LU-10 in spheroids. However, under aerobic conditions with a 10% fraction of hypoxic cells, there was more toxicity than would be predicted from simple additivity. Xenografts treated with 131I-NR-LU-10 + SR 4233 had a growth delay that was significantly longer than that achieved with 131I-NR-LU-10 alone. In both spheroids and xenografts, combined treatment produced about 10 times more cell killing than 131I-NR-LU-10 alone. The lack of enhancement in spheroids under complete hypoxia suggests that SR 4233 does not sensitize hypoxic cells to radiation damage. The results with aerobic spheroids and in vivo, where a portion of the cells were hypoxic, could be explained by the targeting of different cell populations (hypoxic and aerobic) by each therapeutic modality. This effect should also be enhanced by reoxygenation and reestablishment of the hypoxic fraction during treatment, thus allowing more than the initially hypoxic fraction of cells to be killed by the SR 4233.
放射免疫疗法受到抗体分子向肿瘤内缓慢渗透的阻碍。由于距离供血血管较远而难以被抗体靶向的细胞，接受的辐射剂量最低，如果存在耐辐射的缺氧细胞，这个问题会更加严重。将放射免疫疗法与对这些细胞具有优先毒性的药物联合使用将会是理想的。SR 4233是一种强效的缺氧细胞毒素，在这些研究中，它与131I-NR-LU-10联合用于治疗LS174T人结肠腺癌多细胞球体和裸鼠异种移植瘤。在严重缺氧（<0.01% O2）条件下，用SR 4233预处理2小时或同时处理18小时，并未显著提高131I-NR-LU-10在球体中的有效性。然而，在缺氧细胞占10%的有氧条件下，毒性比简单相加预测的要大。用131I-NR-LU-10 + SR 4233治疗的异种移植瘤的生长延迟明显长于单独使用131I-NR-LU-10。在球体和异种移植瘤中，联合治疗产生的细胞杀伤作用比单独使用131I-NR-LU-10大约高10倍。在完全缺氧条件下球体中缺乏增强作用表明SR 4233不会使缺氧细胞对辐射损伤敏感。有氧球体和体内实验（其中一部分细胞是缺氧的）的结果可以通过每种治疗方式对不同细胞群体（缺氧和有氧）的靶向作用来解释。在治疗过程中，再氧化和缺氧部分的重新建立也应会增强这种效应，从而使更多最初并非缺氧的细胞被SR 4233杀死。
