Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.
Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.
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DOI：
10.1007/s10637-011-9692-7
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发表时间：
2012-08-01
影响因子：
3.4
通讯作者：
Schwartz, Laurent
中科院分区：
文献类型：
--
作者：
Abolhassani, Mohammad;Guais, Adeline;Schwartz, Laurent
已知代谢途径的改变是癌症的特征。然而，为了抑制癌症生长，必须同时靶向参与这些途径的多种蛋白质。我们已经开发了一种筛选方法，以评估基于靶向肿瘤特异性代谢中涉及的几个因素的癌症治疗的最佳药物组合。在回顾了文献之后，我们确定了那些已知在癌症中失调的酶，并建立了一个62种靶向药物的列表。这些分子在临床环境中常规用于癌症以外的疾病。我们针对四种细胞系在体外筛选第一文库，然后针对三种鼠同系癌症模型（LL/2，刘易斯肺癌; B16-F10，黑色素瘤;和MBT-2，膀胱癌）在体内评估最有希望的二元组合。使用α-硫辛酸和羟基柠檬酸盐（METABLOCTM）的组合获得最佳结果。在本研究中，通过对大量组合进行体内评价，添加了第三种药物。与顺铂相比，奥曲肽的添加在相同模型中强烈地减少肿瘤发展（T/C%值为30.2至34.5%; P < 0.001），并延长动物存活（P < 0.001）。这些结果在不同的实验室环境中使用人异种移植模型（NCI-H69，小细胞肺癌）得到证实。已知这三种分子都不靶向DNA。这种组合在几种动物模型中的有效性，以及这些廉价药物的低毒性，强调了迅速建立临床试验的必要性。
Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of alpha-lipoic acid and hydroxycitrate (METABLOC(TM)). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.