In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia
In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia
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DOI：
10.1158/1078-0432.ccr-09-1296
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发表时间：
2009-11-01
影响因子：
11.5
通讯作者：
Chen, Qian-Ming
中科院分区：
文献类型：
--
作者：
Li, Yi;Li, Long-Jiang;Chen, Qian-Ming
目的：口腔白斑是一种公认的鳞癌癌前病变。当伴有P53异常表达时，其癌变风险更高。本研究旨在检测重组人腺病毒-P53能否将野生型P53基因导入口腔白斑细胞，诱导细胞周期停滞和细胞凋亡。实验设计：选择P53(-)口腔异型角质形成细胞POE-9n，观察其对POE-9N细胞的生长抑制、细胞周期改变、细胞凋亡抑制作用，并阐述重组腺病毒-P53对POE-9N细胞的相应分子机制。同时，对22例增生性口腔白斑患者多点上皮内注射重组腺病毒-P53的可行性、安全性和生物学活性进行了评价。结果：重组腺病毒-P53可成功地将外源P53导入POE-9n细胞。本研究的最佳感染滴度为感染复数(MOI)=100。重组腺病毒-P53通过诱导p21(CIP/WAF)和下调bcl2的表达，强烈抑制POE-9N细胞的增殖，诱导细胞凋亡，使细胞周期停滞于G期。治疗后P53蛋白和p21(CIP/WAF)蛋白表达明显增强，而bcl2蛋白低表达。16例临床有效，14例组织病理学明显改善。结论：上皮内注射重组人腺病毒-P53治疗异型口腔白斑安全、可行、具有生物学活性。(临床癌症研究2009；15(21)：6724-31)
Purpose: Oral leukoplakia is a well-recognized precancerous lesion of squamous cell carcinoma. When accompanied with abnormal p53 expression, it suffered a higher risk of canceration. The present study was carried out to test whether the recombinant human adenovirus-p53 could introduce wild-type p53 gene to oral leukoplakia cells and induce cell cycle arrest and apoptosis.Experimental Design: We select p53(-) oral dysplastic keratinocyte POE-9n, to observe the growth inhibition, cell cycle change, apoptosis-incluced effects, and elaborate the corresponding molecular mechanism of recombinant adenovirus-p53 on POE-9n cells. Meanwhile, we evaluate the feasibility, safety, and biological activity of multipoints intraepithelial injections of recombinant adenovirus-p53 in 22 patients with dysplastic oral leukoplakia.Results: Exogenous p53 could be successfully transduced into POE-9n cells by recombinant adenovirus-p53. The optimal infecting titer in this study was multiplicity of infection (MOI) = 100. Recombinant adenovirus-p53 could strongly inhibit cell proliferation, induce apoptosis, and arrest cell cycle in stage G, in POE-9n cells by inducing p21(CIP/WAF) and downregulating bcl-2 expression. In the posttreatment patients, p53 protein and p21(CIP/WAF) protein expression were significantly enhanced, yet bcl-2 protein presented low expression. Sixteen patients showed clinical response to the treatment, and 14 patients showed obvious histopathologic improvement.Conclusion: Intraepithelial injections of recombinant human adenovirus-p53 were safe, feasible, and biologically active for patients with dysplastic oral leukoplakia. (Clin Cancer Res 2009; 15(21):6724-31)