In vivo expression and antitumor activity of p53 gene transfer with naked plasmid DNA in an ovarian cancer xenograft model in nude mice
In vivo expression and antitumor activity of p53 gene transfer with naked plasmid DNA in an ovarian cancer xenograft model in nude mice
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DOI：
10.1111/j.1447-0756.2006.00435.x
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发表时间：
2006-10-01
影响因子：
1.6
通讯作者：
Quesnel, Bruno
中科院分区：
文献类型：
--
作者：
Collinet, Pierre;Vereecque, Rodolphe;Quesnel, Bruno
简介：p53 和 p16 肿瘤抑制基因的异常是与人类肿瘤相关的最常见现象之一。因此，野生型 p53 或 p16 功能的恢复被视为癌症基因治疗的一种特别有前途的方法。体外和体内数据表明，病毒介导的p53基因转移可以诱导主动细胞死亡和卵巢肿瘤消退。目的：评价瘤内注射裸DNA在卵巢异种移植模型中抑制肿瘤生长的效率。为此，使用单独或组合编码野生型p53(wt-p53)或p16的质粒载体。方法：给裸鼠皮下注射人卵巢腺癌细胞系SKOV3。异种移植后三周，荷瘤小鼠每周两次注射携带WT-p53和/或WT-p16 cDNA的质粒载体。使用空质粒和盐水缓冲液作为对照。监测肿瘤生长以评估p53和/或p16恢复的抑制潜力。结果：与对照相比，瘤内重复注射编码wt-p53的裸露质粒DNA抑制肿瘤生长。 p16 没有观察到这种抑制作用，并且 p53 和 p16 之间不能获得协同作用。注射编码 wt-p53 的质粒后，84% 的小鼠恢复了 p53 表达。注射 p16 编码质粒的小鼠中有 63% 恢复了 p16 表达。结论：在本报告中，我们证明：(i) 裸露 DNA 代表 SKOV3 异种移植模型中的有效基因转移； (ii)恢复wt-p53基因可以抑制肿瘤生长； (iii) 这种抑制可能与 p53 表达相关，如在重复裸 DNA 注射后 84% 的治疗小鼠中观察到的。这些结果使我们能够设想将裸DNA作为卵巢癌治疗的辅助剂，同时进行肿瘤切除和化疗。
Introduction: Abnormalities in the p53 and p16 tumor suppressor genes are one of the most common occurrences associated with human neoplasia. Consequently, restoration of wild-type p53 or p16 functions is seen as a particularly promising approach for cancer gene therapy. In vitro and in vivo data have demonstrated that virus-mediated p53 gene transfer can induce active cell death and ovarian tumor regression.Aim: To evaluate the efficiency of intratumoral injection of naked DNA in tumor growth inhibition in an ovarian xenograft model. For that purpose, plasmid vectors encoding wild-type p53 (wt-p53) or p16 alone or in combination were used.Methods: Nude mice were injected subcutaneously with the human ovarian adenocarcinoma cell line SKOV3. Three weeks after xenograft, tumor-bearing mice were injected twice a week with plasmid vectors carrying WT-p53 and/or WT-p16 cDNA. Empty plasmids and saline buffer were used as control. Tumor growth was monitored to evaluate the inhibition potential with p53 and/or p16 restoration.Results: When compared to the control, intratumoral repeated injections of naked plasmid DNA encoding wt-p53 were inhibiting tumor growth. This inhibition was not observed with p16 and no synergy could be obtained between p53 and p16. p53 expression was restored in 84% of mice injected with plasmid encoding wt-p53. p16 expression was restored in 63% of mice injected with plasmid encoding p16.Conclusions: In this report we demonstrated that: (i) naked DNA represents an efficient gene transfer in the SKOV3 xenograft model; (ii) restoration of wt-p53 gene allows tumor growth inhibition; and (iii) this inhibition could be correlated with p53 expression as seen in 84% of treated mice after repeated naked DNA injections. These results allow us to envisage naked DNA as a therapeutic adjuvant in ovarian cancer treatment, concomitantly with tumor resection and chemotherapy.