Kizaka-Kondoh Shinae, Inoue Masahiro, Harada Hiroshi, Hiraoka Masahiro
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, 54 Shongoin Kawahararcho, Sakyo-ku, Kyoto 606-8507.
Cancer Sci. 2003 Dec;94(12):1021-8. doi: 10.1111/j.1349-7006.2003.tb01395.x.
Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO(2) < 0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties.
肿瘤缺氧被认为是一个潜在的治疗难题，因为它使实体瘤对低线性能量传递辐射（IR）和化疗药物更具抗性。此外，最近的实验室和临床数据表明，肿瘤缺氧还与各种实体瘤患者更恶性的表型和较差的生存率相关。因此，人们探索了对缺氧肿瘤细胞的选择性靶向，并且由于正常组织中不会出现严重缺氧（pO₂ < 0.33%，2.5 mmHg），肿瘤缺氧可被用于治疗优势。然而，缺氧肿瘤区域的以下三个特征在靶向缺氧细胞方面构成了障碍。首先，难以将足够量的药物输送到远离血管的区域。其次，必须特异性地靶向缺氧肿瘤细胞，同时使正常富氧组织免受损伤。最后，要攻击的严重缺氧肿瘤细胞通常已经停止分裂。因此，高递送效率、高特异性和选择性细胞毒性对于靶向和对抗缺氧肿瘤细胞都是必要的。本综述描述了肿瘤缺氧生物学方面的进展，并汇编了最近用于靶向缺氧肿瘤的分子方法。这些方法包括我们使用一种独特的缺氧靶向蛋白药物TOP3的工作，我们试图用它来解决上述三个难题。
