Sartorelli A C, Hodnick W F, Belcourt M F, Tomasz M, Haffty B, Fischer J J, Rockwell S
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Oncol Res. 1994;6(10-11):501-8.
Hypoxic cells of solid tumors represent a therapeutically resistant population that limits the curability of many solid tumors by x-irradiation and by most chemotherapeutic agents. The oxygen deficit, however, creates an environment conducive to reductive processes that results in a major exploitable difference between normal and neoplastic tissues. Mitomycin C (MC) can be reductively activated by a number of oxidoreductases, in a process required for the production of its therapeutic effects. This enzymatic reduction results in preferential activation of MC under hypoxia and, in most instances, the production of greater toxicity to oxygen-deficient cells than to their oxygenated counterparts. DNA appears to be the most important target of the reactive species generated from MC, with both mono- and bis-adducts of DNA being formed in drug-treated cells. The demonstration that MC, used to kill the hypoxic fraction, in combination with x-irradiation, to eradicate the oxygenated portion of the tumor, produced enhanced cytodestructive effects on solid tumors of animals has led to the clinical evaluation of the mitomycin antibiotics in combination with x-rays in patients with cancers of the head and neck. The findings from these clinical trials have demonstrated the utility of directing a concerted therapeutic attack on the hypoxic fraction of solid tumors as an approach toward enhancing the curability of localized neoplasms by x-irradiation.
实体瘤中的缺氧细胞代表了一个具有治疗抗性的群体，它限制了许多实体瘤通过X射线照射和大多数化疗药物治愈的可能性。然而，缺氧环境创造了有利于还原过程的条件，这导致了正常组织和肿瘤组织之间存在一个主要的可利用差异。丝裂霉素C（MC）可以被多种氧化还原酶还原激活，这是其产生治疗效果所必需的过程。这种酶促还原导致MC在缺氧条件下优先被激活，并且在大多数情况下，对缺氧细胞产生的毒性比对其富氧对应细胞更大。DNA似乎是MC产生的反应性物种的最重要靶点，在药物处理的细胞中会形成DNA的单加合物和双加合物。有证据表明，用于杀死缺氧部分的MC与X射线照射联合使用，以根除肿瘤的富氧部分，对动物实体瘤产生了增强的细胞破坏作用，这促使人们对丝裂霉素类抗生素与X射线联合用于头颈癌患者进行临床评估。这些临床试验的结果表明，针对实体瘤的缺氧部分进行协同治疗攻击，作为一种通过X射线照射提高局部肿瘤治愈率的方法是有用的。
