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Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy
Lizzia Raffaghello*, Changhan Lee, Fernando M. Safdie, Min Wei, Federica Madia, Giovanna Bianchi*, and Valter D. Longo,
Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191; and *Laboratory of Oncology, Giannina Gaslini Institute, 16147 Genova, Italy
Edited by Joan Selverstone Valentine, University of California, Los Angeles, CA, and approved February 11, 2008 (received for review August 29, 2007)
Abstract
Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val19. Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.
美国加州科学家以老鼠作实验，发现接受化疗的老鼠如果禁食48小时，在化疗后不但体内绝大部分的癌细胞被消灭，而且还能免受密集化疗产生的副作用的影响。如果此法用在人身上，也能产生这样的现象，那癌症病人不只能够免受化疗药物的摧残，医生也能向病人下重药，进行更为激烈的治疗。
据新加坡《联合早报》4月1日报道，美国南加州大学研究人员隆哥说：“我们使用非常高剂量的化疗，但这些老鼠还是活动如常。”隆哥小组已向当局提出申请，在一些癌症病人身上展开试验。该小组也在尝试，通过其他办法，比如药物或特别饮食，而不是真的禁食，来达到同样效果。
以前就曾发现，饥饿疗法对预防热休克、阻断自发性肿瘤的生长、以及防止扑热息痛(acetaminophen)导致的肝细胞死亡有作用。在最新研究中，隆哥小组用酵母、人体细胞和老鼠细胞，试验饥饿方法对化疗药物的反应，然后又给老鼠注射了一种影响儿童的高致命性癌症细胞，再观察其反应，效果非常明显。
饥饿的酵母对压力和毒性的耐受力增加到1000倍，而挨饿的人体细胞和老鼠细胞，对化疗药物的抵抗力增强10倍；在这同时，癌细胞因为饥饿变弱了。该研究小组在美国《国家科学院院刊》（PNAS）上发表论文说，试验老鼠接受了相当于人体最大允许剂量三至五倍的化学药物以后，“没有明显的压力或疼痛迹象”。
虽然老鼠两天里失去20%的体重，但在化疗四天后基本恢复了；那些挨饿60小时、失去40%体重的老鼠，也在一星期里恢复了正常。超过一半没有挨饿的老鼠化疗后死亡，活下来的也减少了20%体重，但是只有二十八分之一挨饿的老鼠化疗后死去。通常被注射致命癌细胞的老鼠活不过30天，但这些挨饿老鼠寿命延长一倍，活了60天。（来源：中新网）
（《国家科学院院刊》（PNAS），10.1073/pnas.0708100105，Lizzia Raffaghello, Valter D. Longo） |
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发表于 2008-4-2 08:32:46