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BJC:Notch抑制剂使结肠癌化疗治疗更有效

来源:生物谷 2013-08-07 20:38

2013年8月7日讯 /生物谷BIOON/--近日,西澳大利亚医学研究所(WAIMR)科学家结肠癌研究中取得了令人振奋的发现,这可能会导致结肠癌患者化疗治疗更有效。

研究结果刚刚公布在新一期的British Journal of Cancer杂志上,这项研究共收集了441名在Sir Charles Gairdner医院接受手术和化疗治疗的大肠癌患者的肿瘤组织。

研究人员发现,在大肠癌中 “Notch信号”基因开启时,会引起肿瘤生迅速长,导致患者存活率较低。

WAIMR研究员Patrick Candy博士说,在结肠癌中过表达的Notch信号,通常在健康成人中的水平较低。但在对结肠癌细胞系的研究中发现,当肿瘤学会了如何开启Notch信号后,他们变得更耐化疗。

新研究提示医疗专业人员能通过够测试这些Notch蛋白的水平,并用它来决定Notch抑制剂药物是否可能会帮助化疗药物更好地工作。

Candy博士说,虽然研究已经拿到了统计学上强有力的研究结果,但显然还有更多的工作需要完成,以帮助Notch抑制剂药物进入到临床实践中。(生物谷:Bioon.com)

Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model

J J Arcaroli, K S Quackenbush, A Purkey, R W Powell, T M Pitts, S Bagby, A C Tan, B Cross, K McPhillips, E-K Song, W M Tai, R A Winn, K Bikkavilli, M VanScoyk, S G Eckhardt and W A Messersmith

Background:Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.

Methods:A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.

Results:We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.

Conclusion:This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

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