Brown J M, Giaccia A J
Department of Radiation Oncology, Stanford University, CA 94305-5468.
Int J Radiat Biol. 1994 Jan;65(1):95-102. doi: 10.1080/09553009414550131.
Since the 1950s, the presence of hypoxic cells in human tumours has been widely regarded as a problem, and a variety of strategies have been developed and tested, both in experimental and clinical studies, to overcome this perceived problem. One of these strategies was the development of bioreductive cytotoxins--drugs which in themselves were relatively innocuous, but when metabolized under hypoxic conditions, became highly cytotoxic, thereby preferentially killing the hypoxic cells. Modelling studies and experimental data with newly developed hypoxic cytotoxins, such as SR 4233 (tirapazamine) and RSU 1069, have led to the realization not only that it is better to kill hypoxic cells in tumours than to radiosensitize or oxygenate them, but also that with these bioreductive cytotoxins hypoxic cells in tumours can be an advantage in cancer therapy. However, to realize the advantage of adding the drug with each radiation dose, the tumour must undergo a process analogous to reoxygenation, which we have termed 'rehypoxiation', by which hypoxic cells are regenerated after each dose of the hypoxic cytotoxin. In addition, we also discuss the fact that hypoxia is a cellular stress which activates many new genes. The activation of these genes will be a major focus for research in coming years and will undoubtedly lead to new approaches in cancer detection and treatment. In summary, the 1990s are bringing a fundamental change in our perception of tumour hypoxia, from a position of being a problem to that of being a solution in cancer treatment.
自20世纪50年代以来，人类肿瘤中缺氧细胞的存在一直被广泛视为一个问题，并且在实验和临床研究中已经开发并测试了多种策略来克服这一被认为的问题。这些策略之一是开发生物还原细胞毒素——这类药物本身相对无害，但在缺氧条件下代谢时会变得具有高度细胞毒性，从而优先杀死缺氧细胞。对新开发的缺氧细胞毒素（如SR 4233（替拉扎明）和RSU 1069）的建模研究和实验数据不仅使人们认识到，杀死肿瘤中的缺氧细胞比使其对辐射敏感或使其复氧更好，而且还认识到，使用这些生物还原细胞毒素，肿瘤中的缺氧细胞在癌症治疗中可能是一个优势。然而，为了实现每次放疗剂量添加药物的优势，肿瘤必须经历一个类似于再氧合的过程，我们将其称为“再缺氧”，即每次给予缺氧细胞毒素后，缺氧细胞会再生。此外，我们还讨论了缺氧是一种激活许多新基因的细胞应激这一事实。这些基因的激活将是未来几年研究的主要重点，无疑将带来癌症检测和治疗的新方法。总之，20世纪90年代正在使我们对肿瘤缺氧的认识发生根本性变化，从将其视为一个问题转变为将其视为癌症治疗中的一个解决方案。
