Therapeutic attack of hypoxic cells of solid tumors: presidential address.
Therapeutic attack of hypoxic cells of solid tumors: presidential address.
复制标题
作者：
A. Sartorelli
实体瘤的缺氧细胞对治疗攻击具有相对的抵抗力。研究表明，缺氧的肿瘤细胞存在于有利于还原反应的环境中，这使得缺氧的细胞对生物还原烷基化试剂特别敏感。丝裂霉素C是一种可用于临床的生物还原烷基化试剂，在体外和体内都能优先杀死缺氧细胞。这种现象至少部分是由于缺氧和充氧的肿瘤细胞对丝裂霉素C的摄取和代谢的差异，最终的关键损害是丝裂霉素抗生素对DNA的交联。丝裂霉素C与X射线相结合，分别攻击缺氧和充氧的肿瘤细胞群，已经在实体瘤植入的小鼠和头颈癌患者中导致了增强的抗肿瘤效果。双香豆素与丝裂霉素联合使用或使用相关的抗生素波非霉素，可以更有效地杀灭缺氧的肿瘤细胞。这些发现支持在实体瘤的潜在治疗方案中使用一种对缺氧肿瘤细胞具有特异性的药物。
Hypoxic cells of solid tumors are relatively resistant to therapeutic assault. Studies have demonstrated that oxygen-deficient tumor cells exist in an environment conducive to reductive reactions making hypoxic cells particularly sensitive to bioreductive alkylating agents. Mitomycin C, the prototype bioreductive alkylating agent available for clinical use, is capable of preferentially killing oxygen-deficient cells both in vitro and in vivo. This phenomenon is at least in part the result of differences in the uptake and metabolism of mitomycin C by hypoxic and oxygenated tumor cells, with the ultimate critical lesion being the cross-linking of DNA by the mitomycin antibiotic. The combination of mitomycin C with X-irradiation, to attack hypoxic and oxygenated tumor cell populations, respectively, has led to enhanced antitumor effects in mice bearing solid tumor implants and in patients with cancer of the head and neck. More efficacious kill of hypoxic tumor cells may be possible by the use of dicoumarol in combination with mitomycin or by the use of the related antibiotic porfiromycin. The findings support the use of an agent with specificity for hypoxic tumor cells in potentially curative regimens for solid tumors.