Sartorelli A C
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Cancer Res. 1988 Feb 15;48(4):775-8.
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.
实体瘤的缺氧细胞对治疗攻击相对具有抗性。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，这使得缺氧细胞对生物还原烷基化剂特别敏感。丝裂霉素C是临床上可用的原型生物还原烷基化剂，能够在体外和体内优先杀死缺氧细胞。这种现象至少部分是由于缺氧和富氧肿瘤细胞对丝裂霉素C的摄取和代谢存在差异，最终的关键损伤是丝裂霉素抗生素使DNA发生交联。丝裂霉素C与X射线联合使用，分别攻击缺氧和富氧的肿瘤细胞群体，已在携带实体瘤植入物的小鼠和头颈部癌症患者中产生了增强的抗肿瘤效果。通过使用双香豆素与丝裂霉素联合或使用相关抗生素卟吩姆，可能更有效地杀死缺氧肿瘤细胞。这些发现支持在实体瘤的潜在治愈方案中使用对缺氧肿瘤细胞具有特异性的药物。
