Melillo Giovanni
Developmental Therapeutics Program, SAIC Frederick, Inc, National Cancer Institute, Frederick, MD 21702, USA.
Cancer Metastasis Rev. 2007 Jun;26(2):341-52. doi: 10.1007/s10555-007-9059-x.
Hypoxia, a decrease in oxygen levels, is a hallmark of solid tumors. Hypoxic cells are more resistant to killing by ionizing radiation and chemotherapy, are more invasive and metastatic, resistant to apoptosis, and genetically unstable. Over the last two decades, the discovery of Hypoxia Inducible Factors, a family of transcription factors crucially involved in the response of mammalian cells to oxygen deprivation, has led to the identification of a molecular target associated with hypoxia suitable for the development of cancer therapeutics. These features of solid tumors may offer a unique opportunity for selective therapeutic approaches. A number of strategies targeting hypoxia and/or Hypoxia Inducible Factors (HIF) have been developed over the last several years and will be described. The exponentially growing interest in therapeutic strategies targeting hypoxia/HIF will undoubtedly generate more active compounds for preclinical and clinical development. A rational development plan aimed to validate target inhibition in preclinical models and early clinical trials is essential for a rapid translation of these agents to the treatment of human cancers.
缺氧，即氧水平降低，是实体瘤的一个标志。缺氧细胞对电离辐射和化疗杀伤更具抗性，更具侵袭性和转移性，抗凋亡，且基因不稳定。在过去二十年里，缺氧诱导因子（一类在哺乳动物细胞对缺氧反应中起关键作用的转录因子家族）的发现，促成了一个与缺氧相关的分子靶点的确定，该靶点适用于癌症治疗药物的开发。实体瘤的这些特征可能为选择性治疗方法提供独特机会。在过去几年里，已经开发出了一些针对缺氧和/或缺氧诱导因子（HIF）的策略，将对其进行描述。对针对缺氧/HIF的治疗策略的兴趣呈指数级增长，无疑将产生更多用于临床前和临床开发的活性化合物。旨在在临床前模型和早期临床试验中验证靶点抑制的合理开发计划，对于将这些药物迅速转化用于人类癌症治疗至关重要。
