Horsman M R, Wood P J, Brown J M
Department of Therapeutic Radiology, Stanford University School of Medicine, CA 94305.
Radiother Oncol. 1989 May;15(1):103-14. doi: 10.1016/0167-8140(89)90123-0.
Nitroaromatic radiosensitizers are effective chemosensitizers in vitro and in vivo. We have used EMT6 tumour cells grown as multicellular spheroids to try and further understand the role that hypoxia plays in this process. Our results show that the cell killing produced in whole spheroids following a 1-h exposure to melphalan (L-PAM) was enhanced by a 3-h pre-exposure to 5 mM misonidazole (MISO), an enhancement ratio of 1.3-1.7 being obtained. Sequentially disaggregating spheroids we also found that both L-PAM toxicity and MISO chemosensitization were relatively constant as a function of depth within the spheroid. The binding of 14C-MISO to spheroid cells, measured by scintillation counting of disaggregated cells and by autoradiography analysis of sectioned spheroids, demonstrated that binding increased with depth. However, cells in the outer layers of the spheroid bound more 14C-MISO than expected with fully aerobic cells, while in the innermost viable cells the binding was less than that measured in cells which were fully radiobiologically hypoxic. This suggests that the majority of viable spheroid cells were at oxygen tensions intermediate between those found in either fully aerobic or radiobiologically hypoxic cells, yet their levels of oxygenation were sufficiently low for MISO chemosensitization to occur.
硝基芳香族放射增敏剂在体外和体内都是有效的化学增敏剂。我们使用了以多细胞球体形式生长的EMT6肿瘤细胞，试图进一步了解缺氧在这个过程中所起的作用。我们的结果表明，在对美法仑（L-PAM）进行1小时暴露之前，先对5 mM米索硝唑（MISO）进行3小时预暴露，可增强整个球体中产生的细胞杀伤作用，增强比为1.3至1.7。通过依次分解球体，我们还发现L-PAM毒性和MISO化学增敏作用作为球体深度的函数相对恒定。通过对分解后的细胞进行闪烁计数以及对切片球体进行放射自显影分析来测量14C-MISO与球体细胞的结合，结果表明结合随深度增加。然而，球体外层的细胞比完全需氧细胞预期的结合了更多的14C-MISO，而在最内层的存活细胞中，结合量少于在完全放射生物学缺氧的细胞中测得的量。这表明大多数存活的球体细胞处于完全需氧或放射生物学缺氧细胞中所发现的氧张力之间的中间水平，但其氧合水平足够低，足以发生MISO化学增敏作用。
