Chaplin D J, Acker B, Olive P L
Medical Biophysics Unit, B.C. Cancer Research Centre, Vancouver, Canada.
Int J Radiat Oncol Biol Phys. 1989 May;16(5):1131-5. doi: 10.1016/0360-3016(89)90267-8.
Previous studies have shown that several vasoactive drugs can selectively reduce blood flow and increase hypoxia in experimental tumor systems. Our studies with one such agent, the vasodilator hydralazine, have clearly demonstrated that it can increase the tumor cytotoxicity of drugs which are known to be more toxic under hypoxic conditions. We have now extended our investigations to determine whether such selective reductions in tumor blood flow induced by hydralazine can increase the tumor cytotoxicity of other classes of cancer chemotherapeutic drugs. Our initial studies have involved the alkylating agent melphalan. Administration of hydralazine (5 mg/kg IP) at various times before or after melphalan results in increased tumor cytotoxicity in the Lewis lung carcinoma. An enhancement factor of between 2 and 3 was obtained in this tumor system. Similar results are observed if the vasodilator cadralazine is used. In contrast to the enhancement of the tumor cytotoxicity of melphalan by hydralazine, systemic toxicity is only increased by a factor of 1.2. Therefore, therapeutic gain may accrue from the use of vasodilating agents in combination with melphalan. Studies using spheroids to establish the mechanism responsible for the enhanced tumor cytotoxicity indicate that both hypoxia and pH can influence melphalan toxicity.
以往的研究表明，在实验性肿瘤系统中，几种血管活性药物可选择性地减少血流量并增加缺氧情况。我们对其中一种药物——血管扩张剂肼屈嗪进行的研究已清楚地表明，它可增强已知在缺氧条件下毒性更强的药物的肿瘤细胞毒性。我们现在扩展了研究，以确定肼屈嗪诱导的肿瘤血流量的这种选择性减少是否会增加其他类癌症化疗药物的肿瘤细胞毒性。我们最初的研究涉及烷化剂美法仑。在美法仑给药之前或之后的不同时间给予肼屈嗪（5毫克/千克腹腔注射），可增加Lewis肺癌的肿瘤细胞毒性。在这个肿瘤系统中获得了2至3的增强因子。如果使用血管扩张剂卡屈嗪，也会观察到类似结果。与肼屈嗪增强美法仑的肿瘤细胞毒性相反，全身毒性仅增加1.2倍。因此，联合使用血管扩张剂与美法仑可能会带来治疗益处。使用球体来确定增强肿瘤细胞毒性的机制的研究表明，缺氧和pH值均可影响美法仑的毒性。
