Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.
Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-08-2581
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发表时间：
2009-03-01
期刊：
影响因子：
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通讯作者：
Rocco JW
中科院分区：
文献类型：
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作者：
Michaud WA;Nichols AC;Mroz EA;Faquin WC;Clark JR;Begum S;Westra WH;Wada H;Busse PM;Ellisen LW;Rocco JW
本研究旨在验证抗细胞凋亡蛋白Bcl2家族蛋白表达升高预示口咽鳞状细胞癌(OPSCC)对同期铂类放化疗疗效差的假说。检测了头颈部鳞状细胞癌(HNSCC)细胞系中Bcl2、Bclxl和Bclw的表达水平及其与顺铂耐药的相关性。采用单因素和多因素分析方法，对接受统一治疗的OPSCC患者进行单因素和多因素分析，以评估Bcl2和Bclxl的表达与放化疗后无瘤生存期的关系。在HNSCC细胞系中，内源性Bcl2的高表达与顺铂耐药的增加有关，实验性的Bcl2过表达促进了顺铂的耐药。在治疗前Bcl2阳性的患者中，治疗失败的风险更大(风险比，5.99；95%可信区间，1.73−20.8；P=0.0014)。相反，内源性Bclxl在体外与顺铂敏感性无关，也与体内复发风险无关(危险比，1.28；95%可信区间，0.39−4.19；P=0.68)。Bcl2的表达与其他临床特征的相关性不能解释Bcl2的预测价值。免疫组织化学检测化疗前活检标本中Bcl2的表达可预测晚期OPSCC对同期铂类放化疗的反应。随着针对Bcl-2及其家族成员的治疗变得可行，这种免疫组织化学评估可以通过识别预后较差的患者亚群，从而帮助个性化治疗，这些患者可能会从此类治疗中受益。
This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy. Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multivariate analyses were used to evaluate the relationship between Bcl-2 and Bcl-XL expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC. In HNSCC cell lines, high endogenous Bcl-2 expression was associated with increased cisplatin resistance, and experimental overexpression of Bcl-2 promoted cisplatin resistance. In patients, tumors positive for Bcl-2 before treatment had greater risk of treatment failure (hazard ratio, 5.99; 95% confidence interval, 1.73−20.8; P = 0.0014). In contrast, endogenous Bcl-XL showed no correlation either with cisplatin sensitivity in the cell line panel in vitro, or with risk of recurrence in vivo (hazard ratio, 1.28; 95% confidence interval, 0.39 − 4.19; P = 0.68). Associations between Bcl-2 expression and other clinical characteristics did not account for the predictive value of Bcl-2. Immunohistochemical assessment of Bcl-2 in pretreatment biopsy specimens can predict response of advanced OPSCC to concurrent platinum-based chemoradiation. As treatments targeting Bcl-2 and its family members become available, this immunohistochemical assessment could help personalize therapy by identifying a subpopulation of patients with a poor prognosis who might benefit from such treatments.