靶向细胞凋亡以克服顺铂耐药性：头颈部癌的一项转化研究
Targeting apoptosis to overcome cisplatin resistance: a translational study in head and neck cancer.
作者信息
Bauer Joshua A, Kumar Bhavna, Cordell Kitrina G, Prince Mark E, Tran Huong H, Wolf Gregory T, Chepeha Douglas B, Teknos Theodoros N, Wang Steven, Eisbruch Avraham, Tsien Christina I, Urba Susan G, Worden Francis P, Lee Julia, Griffith Kent A, Taylor Jeremy M G, D'Silva Nisha, Wang Shaomeng J, Wolter Keith G, Henson Bradley, Fisher Susan G, Carey Thomas E, Bradford Carol R
机构信息
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
出版信息
Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S106-8. doi: 10.1016/j.ijrobp.2007.05.080.
PURPOSE
Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed.
METHODS AND MATERIALS
Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL.
RESULTS
HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC.
CONCLUSION
Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53.
目的
顺铂耐药仍然是晚期头颈部鳞状细胞癌（HNSCC）患者器官保留和生存的障碍。正在开发克服顺铂耐药性HNSCC的靶向治疗方法。
方法和材料
研究了顺铂敏感的亲本HNSCC细胞系和顺铂耐药的子代细胞系。使用预处理的HNSCC活检组织构建组织微阵列，对其进行p53和Bcl-xL染色。
结果
选择的顺铂耐药HNSCC细胞系具有野生型p53和高水平的Bcl-xL。在Bcl-xL水平低的细胞系中野生型p53的表达增强了顺铂敏感性。Bcl-xL和野生型p53的表达均使肿瘤细胞对顺铂产生耐药性。肿瘤表达低水平p53和Bcl-xL的患者器官保留情况和无病生存期最佳，而肿瘤表达低水平p53和高水平Bcl-xL的患者预后最差。抑制Bcl-xL或激活p53功能的新型药物可能靶向顺铂耐药性HNSCC。
结论
HNSCC中的顺铂耐药性至少部分由高Bcl-xL和功能性p53介导。
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