Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component.
Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component.
复制标题
利用 HSVtk 基因的组织特异性表达对小鼠黑色素瘤进行全身基因治疗涉及免疫成分。
作者：
R. Vile;J. Nelson;S. Castleden;H. Chong;I. Hart
以前，我们已经证明了安全和有效的转移HSVtk细胞毒性基因的主要小鼠黑色素瘤肿瘤直接注射的质粒和逆转录病毒载体，其中HSVtk基因是由组织特异性酪氨酸酶启动子驱动。然而，对于一般的临床应用，理想地，这种形式的治疗应该对播散性转移有效。我们在这里报告说，最近建立的B16黑色素瘤的肺转移的C57 BL小鼠更昔洛韦治疗的数量减少，与对照组相比，多次静脉注射高滴度逆转录病毒上清液编码的HSVtk基因，但不是在管理后的脂质体复合质粒DNA。使用聚合酶链反应分析，整合的前病毒中观察到转移轴承肺（4 6只小鼠）和脾脏中的一些更昔洛韦治疗的动物（2 6只小鼠），但不是在睾丸，脑，心脏，肝脏，或肾脏。C57 BL小鼠中实验转移瘤数量的减少超过了预期的肿瘤细胞转导程度，这表明存在明显的旁观者效应。在免疫缺陷的无胸腺小鼠中没有观察到这种程度的减少，表明免疫系统在旁观者效应中起一定作用。在支持这些数据，我们表明，而父母的肿瘤细胞只有很差的免疫原性，一个有效的抗肿瘤免疫反应产生后，杀死体内的肿瘤细胞作为治疗的结果更昔洛韦。这些效应可能是负责增强逆转录病毒感染的疗效。通过HSVtk/更昔洛韦系统的局部细胞杀伤和抗肿瘤免疫的诱导的组合提示用于癌症的基因治疗的载体的设计的新的机会。
Previously we have demonstrated safe and effective transfer of the HSVtk cytotoxic gene to primary murine melanoma tumors by direct injection of plasmid and retroviral vectors in which the HSVtk gene is driven by the tissue-specific tyrosinase promoter. However, for general clinical application such forms of therapy should, ideally, be effective against disseminated metastases. We report here that the number of recently established lung metastases of B16 melanoma in C57BL mice treated with ganciclovir is reduced compared to controls after multiple i.v. administrations of high titer retroviral supernatant encoding the HSVtk gene, but not after administration of liposome-complexed plasmid DNA. Using polymerase chain reaction analysis, integration of the provirus was observed in metastasis-bearing lungs (4 of 6 mice) and in the spleens of some ganciclovir-treated animals (2 of 6 mice) but not in the testes, brain, heart, liver, or kidney. The reduction in the number of experimental metastases in C57BL mice exceeded the anticipated extent of transduction of tumor cells, which is indicative of a marked bystander effect. This magnitude of reduction was not observed in immunodeficient athymic mice, suggesting that the immune system plays some part in the bystander effect. In support of these data, we show that, whereas the parental tumor cells are only poorly immunogenic, an effective antitumor immune response is generated following the killing of neoplastic cells in vivo as a result of treatment with ganciclovir. These effects may be responsible for augmenting the efficacy of retroviral infection. The combination of local cell killing by the HSVtk/ganciclovir system and the induction of antitumor immunity suggests new opportunities for the design of vectors for the gene therapy of cancer.
登录
查看更多内容
通过气管内滴注逆转录病毒反义 K-ras 构建体来预防原位人肺癌生长。
影响因子：
11.2
作者：
Georges,RN;Mukhopadhyay,T;Zhang,Y;Yen,N;Roth,JA
通讯作者：
Roth,JA
克服逆转录病毒重复感染的干扰会导致克隆基因的表达和传播放大。
DOI：
10.1073/pnas.85.15.5404
发表时间：
1988
影响因子：
11.1
作者：
Bestwick,RK;Kozak,SL;Kabat,D
通讯作者：
Kabat,D
影响因子：
3.7
作者：
MARKOWITZ, D;GOFF, S;BANK, A
通讯作者：
BANK, A
DOI：
10.1073/pnas.90.23.11307
发表时间：
1993-12-01
影响因子：
11.1
作者：
NABEL, GJ;NABEL, EG;CHANG, AE
通讯作者：
CHANG, AE
重组腺病毒介导的人肺癌细胞中野生型p53的高效基因转移和高水平表达。
影响因子：
6.4
作者：
Zhang,WW;Fang,X;Mazur,W;French,BA;Georges,RN;Roth,JA
通讯作者：
Roth,JA