THERAPEUTIC EFFECT OF A RETROVIRAL WILD-TYPE P53 EXPRESSION VECTOR IN AN ORTHOTOPIC LUNG-CANCER MODEL
THERAPEUTIC EFFECT OF A RETROVIRAL WILD-TYPE P53 EXPRESSION VECTOR IN AN ORTHOTOPIC LUNG-CANCER MODEL
复制标题
DOI：
10.1093/jnci/86.19.1458
复制
发表时间：
1994-10-05
期刊：
影响因子：
--
通讯作者：
ROTH, JA
中科院分区：
文献类型：
--
作者：
FUJIWARA, T;CAI, DW;ROTH, JA
背景：p53 抑癌基因（也称为 TP53）突变在人类肺癌中很常见。 p53 的野生型形式比突变体占优势；因此，恢复肺癌细胞中野生型p53的功能可能会抑制它们作为肿瘤的生长。目的：我们研究了在 nu/nu 小鼠原位人肺癌模型中直接施用逆转录病毒野生型 p53 (wt-p53) 表达载体 (LNp53B) 的治疗效果。方法：体外感染LNp53B后通过细胞计数测定H226Br细胞的增殖情况。受辐射（350 cGy）的雌性 BALB/c nu/nu 小鼠气管内接种 2 x 10(6) H226Br 细胞（其 p53 基因在密码子 254 处有纯合突变），并在 3 天后开始气管内滴注 LNp53B 逆转录病毒上清液治疗 3 天。结果：LNp53B感染体外抑制H226Br细胞增殖。肿瘤细胞接种30天后，62%-80%的对照小鼠出现右主干支气管肉眼可见的肿瘤。 LNp53B 抑制了 62%-100% 小鼠的 H226Br 肿瘤形成，并且通过用无活性载体稀释逆转录病毒上清液消除了该效果。结论：直接给予表达wt-p53的逆转录病毒载体可以抑制p53表达异常的人肺癌细胞体内局部生长。意义：基于目标癌症中发现的突变类型开发基因替代治疗策略是必要的，并且可能导致肺癌新辅助疗法和基因特异性预防策略的开发。
Background: Mutations in the p53 tumor suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumors. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 cGy) female BALB/c nu/nu mice were inoculated intratracheally with 2 x 10(6) H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an intratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62%-80% of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62%-100% of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer.