Ferguson L R, Turner P M
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Eur J Cancer Clin Oncol. 1988 Apr;24(4):591-6. doi: 10.1016/0277-5379(88)90286-6.
The mitochondria of cancer cells are potential targets for chemotherapy. Drugs which primarily affect mitochondrial DNA can be screened using a 'petite' mutagenesis assay in Saccharomyces cerevisiae. We have used this approach to estimate the antimitochondrial effects of a range of current clinical and experimental antitumour drugs with varying modes of action. Of agents currently in the clinic, the antimetabolites 5-fluorouracil and methotrexate were extremely effective in inducing this respiratory defect, providing cells were growing during treatment. Adriamycin, BCNU, bleomycin, methyl CCNU, cis-platinum, chlorambucil, daunomycin, nitracine, nitrogen mustard and hycanthone were also weakly effective 'petite' mutagens, in either growing or non-growing conditions. None of the currently used agents but some experimental drugs induced high numbers of 'petite' mutants during growing or non-growing conditions. To date, where such agents have been tested clinically, they have proved either ineffective or very toxic. It is possible that antimitochondrial effects on non-proliferating cellular tissues such as the heart might cause unacceptable toxicity and preclude the clinical use of such agents. For those agents effective against proliferating cells, the mitochondria could be an important target for chemotherapy in some cell types. This type of drug appears relatively uncommon in the clinic at present. The 'petite' mutagenesis assay could be more widely used as a screen to optimize this property in development of analogues of current clinical agents, or in developing new types of anticancer drug.
癌细胞的线粒体是化疗的潜在靶点。主要影响线粒体DNA的药物可通过酿酒酵母中的“小菌落”诱变试验进行筛选。我们已采用这种方法来评估一系列目前临床使用的和实验用的、具有不同作用方式的抗肿瘤药物的抗线粒体效应。在目前临床使用的药物中，抗代谢物5-氟尿嘧啶和甲氨蝶呤在诱导这种呼吸缺陷方面极其有效，前提是细胞在治疗期间处于生长状态。阿霉素、卡氮芥、博来霉素、甲基环己亚硝脲、顺铂、苯丁酸氮芥、柔红霉素、硝吖嗪、氮芥和海蒽酮在生长或非生长条件下也是弱效的“小菌落”诱变剂。目前使用的药物中没有一种，但一些实验药物在生长或非生长条件下能诱导大量“小菌落”突变体。迄今为止，在对这些药物进行临床测试的地方，它们要么无效，要么毒性很大。对心脏等非增殖性细胞组织的抗线粒体效应可能会导致不可接受的毒性，从而排除这些药物的临床应用。对于那些对增殖细胞有效的药物，线粒体可能是某些细胞类型化疗的重要靶点。目前这类药物在临床上似乎相对少见。“小菌落”诱变试验可更广泛地用作一种筛选方法，以在开发当前临床药物的类似物或新型抗癌药物时优化这一特性。
