Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector
Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector
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DOI：
10.1006/mthe.2001.0266
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发表时间：
2001-03-01
影响因子：
12.4
通讯作者：
Roth, JA
中科院分区：
文献类型：
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作者：
Ramesh, R;Saeki, T;Roth, JA
由于缺乏有效的载体传递系统，将治疗基因传递到播散性肿瘤部位一直是癌症基因治疗领域的主要挑战。在目前可用的各种载体中，脂质体已显示出将基因以最小毒性系统递送到远端部位的希望。在本报告中，我们描述了一种改进的挤压DOTAP：胆固醇（DOTAP:Chol）阳离子脂质体，它能有效地将肺癌中经常改变的治疗性肿瘤抑制基因p53和FHIT传递给局限性人类原发性肺癌和实验性弥散性转移瘤。在原发肿瘤中，每个肿瘤中有25%的肿瘤细胞表达转基因，在播散性肿瘤中有10%的肿瘤细胞表达转基因。当使用DOTAP: cholo -p53和-FHIT复合物治疗时，观察到原发性（P < 0.02）和转移性肺肿瘤的生长均有显著抑制（P < 0.007）。此外，与单一治疗相比，重复多次治疗显示基因表达增加2.5倍，治疗效果也有所提高。最后，动物生存实验显示，脂质体-p53 DNA复合物处理延长了动物的生存时间（中位生存时间：76天，H1299组P < 0.001； A549组96天，P = 0.04）。我们的发现可能对发展原发性和播散性人类肺癌的治疗具有重要意义。
Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP: Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.