Poirson-Bichat F, Gonçalves R A, Miccoli L, Dutrillaux B, Poupon M F
Institut Curie, UMR 147 CNRS-Institut Curie, Paris, France.
Clin Cancer Res. 2000 Feb;6(2):643-53.
Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-dependent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the efficacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting the exogenous methionine (Met) supply and ethionine. Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathione pools so as to sensitize tumors refractory to cytotoxic anticancer drugs. Met depletion was achieved by feeding mice a methionine-free diet supplemented with homocysteine. The effects of Met depletion combined with ethionine and/or chemotherapeutic agents were studied using human solid cancers xenografted into nude mice. TC71-MA (a colon cancer) SCLC6 (a small cell lung cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, doxorubicin, and carmustine, respectively. These three drugs are used to treat such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6, and SNB19 were Met dependent because their proliferation in vitro and growth in vivo were reduced by Met depletion. Cisplatin was inactive in the treatment of TC71-MA colon cancer, whereas a methionine-free diet, alone or in combination with ethionine, prolonged the survival of mice by 2-fold and 2.8-fold, respectively. When all three approaches were combined, survival was prolonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1-MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination with doxorubicin, an inhibition of 51% was obtained, with survival prolonged by 1.7-fold. Combined treatment produced greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretreated with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustine, but when it was combined with Met depletion, survival duration was prolonged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemotherapeutic agents on drug-refractory tumors.
在许多肿瘤中，化疗的疗效受到特定细胞机制的限制，这些机制会使细胞毒性抗肿瘤药物失活，比如ATP依赖的药物外排和/或谷胱甘肽介导的药物解毒作用。通过减少ATP储备和/或谷胱甘肽合成，有可能增强受此类耐药机制影响的药物的疗效。通过耗尽外源性甲硫氨酸（Met）供应和乙硫氨酸，可以使癌细胞中的ATP储备和谷胱甘肽含量降低。因此，本研究的基本原理是利用Met耗竭来减少ATP和谷胱甘肽储备，从而使对细胞毒性抗癌药物难治的肿瘤变得敏感。通过给小鼠喂食补充了同型半胱氨酸的无甲硫氨酸饮食来实现Met耗竭。使用移植到裸鼠体内的人实体癌研究了Met耗竭联合乙硫氨酸和/或化疗药物的效果。发现TC71-MA（一种结肠癌）、SCLC6（一种小细胞肺癌）和SNB19（一种神经胶质瘤）分别对顺铂、阿霉素和卡莫司汀耐药。这三种药物用于治疗此类肿瘤，其活性依赖于缺乏细胞ATP或谷胱甘肽依赖性耐药机制。TC71-MA、SCLC6和SNB19依赖Met，因为Met耗竭会降低它们在体外的增殖和在体内的生长。顺铂对TC71-MA结肠癌的治疗无效，而无甲硫氨酸饮食单独或与乙硫氨酸联合使用，分别使小鼠的生存期延长了2倍和2.8倍。当三种方法联合使用时，生存期延长了3.3倍。阿霉素对表达MDR1-MRP的肿瘤SCLC6的生长没有影响。缺乏Met的饮食和乙硫氨酸略微降低了SCLC6的生长，与阿霉素联合使用时，抑制率达到51%，生存期延长了1.7倍。联合治疗在先用阿霉素预处理的SCLC6肿瘤SCLC6-Dox中产生了更大的肿瘤生长抑制（74%）。卡莫司汀没有抑制SNB19神经胶质瘤的生长，但与Met耗竭联合使用时，生存期延长了2倍，生长抑制率为80%。这些结果表明Met耗竭有可能增强化疗药物对耐药肿瘤的抗肿瘤作用。
