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JNCI:研究揭示结肠癌为什么会抵抗化疗

来源:生物谷 2013-12-03 20:19

2013年12月3日讯 /生物谷BIOON/--在肿瘤临床治疗领域中常​​观察到的现象是:肿瘤病人接受药物,起初反应非常好,但几个月后,肿瘤复发,并且对原先的治疗药物出现耐药性。

这其中发生了什么事?虽然许多机制有助于解释这种效应-- “获得性抗性”,但近日,巴塞罗那大学Manel Esteller教授小组在The Journal of The National Cancer Institute杂志上发表文章证实:表观遗传差异的存可用来解释药物对复发肿瘤缺乏反应的原因。

Manel Esteller解释:我们研究结肠癌细胞,结肠癌细胞最初对奥沙利铂药物敏感,然后一段时间后会对这种药物不敏感,我们发现,抗性肿瘤细胞DNA中基因(SRBC)失活,SRBC基因参与DNA的修复。研究了近200例结肠癌,还发现该基因的失活与患者的生存较差有关。

Esteller进一步阐述:有趣的是该基因的功能丧失也可以解释为什么一些结肠肿瘤性从一开始就被称为“原发性耐药”。这一发现可能对结肠癌的个性化治疗具有重要意义。

如果这些结果扩展到其它临床试验中,确定SRBC基因的激活状态可以用来决定患者是否应该接收某一类药物或其它药物额治疗。最后,新研究还有助于检查类似的机制是否发生在结肠癌以外的人类肿瘤类型中。(生物谷Bioon.com)

Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer

Catia Moutinho, Anna Martinez-Cardús, Cristina Santos, Valentin Navarro-Pérez, Eva Martínez-Balibrea, Eva Musulen, F. Javier Carmona, Andrea Sartore-Bianchi, Andrea Cassingena, Salvatore Siena, Elena Elez, Josep Tabernero, Ramon Salazar, Albert Abad and Manel Esteller

Background A major problem in cancer chemotherapy is the existence of primary resistance and/or the acquisition of secondary resistance. Many cellular defects contribute to chemoresistance, but epigenetic changes can also be a cause.

Methods A DNA methylation microarray was used to identify epigenetic differences in oxaliplatin-sensitive and -resistant colorectal cancer cells. The candidate gene SRBC was validated by single-locus DNA methylation and expression techniques. Transfection and short hairpin experiments were used to assess oxaliplatin sensitivity. Progression-free survival (PFS) and overall survival (OS) in metastasic colorectal cancer patients were explored with Kaplan–Meier and Cox regression analyses. All statistical tests were two-sided.

Results We found that oxaliplatin resistance in colorectal cancer cells depends on the DNA methylation–associated inactivation of the BRCA1 interactor SRBC gene. SRBC overexpression or depletion gives rise to sensitivity or resistance to oxaliplatin, respectively. SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%; n = 39 of 131), where it predicted shorter PFS (hazard ratio [HR] = 1.83; 95% confidence interval [CI] = 1.15 to 2.92; log-rank P = .01), particularly in oxaliplatin-treated case subjects for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13 to 3.40; log-rank P = .01). In a validation cohort of unresectable colorectal tumors treated with oxaliplatin (n = 58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; 95% CI = 1.01 to 3.60; log-rank P = .045).

Conclusions These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.

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