Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy
Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy
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DOI：
10.1038/sj.cgt.7700941
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发表时间：
2006-07-01
影响因子：
6.4
通讯作者：
Dong, Z.
中科院分区：
文献类型：
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作者：
Olson, M. V.;Lee, J.;Dong, Z.
我们之前报道过腺病毒载体介导的干扰素(IFN)- β基因治疗可抑制裸鼠人前列腺癌细胞的原位生长。本研究的目的是确定该疗法在免疫能力小鼠中的疗效和机制。用100倍感染倍数（MOI）编码小鼠ifn - β (adifn - β)的腺病毒载体(而不是AdE/1（对照腺病毒载体）感染了TRAMP-C2Re3小鼠前列腺癌细胞后，大约每24小时产生60 ng/10(5)个细胞的ifn - β。adifn - β转导细胞在C57BL/6小鼠前列腺中的致瘤性显著降低。单次瘤内注射2 × 10(9) PFU（斑块形成单位）的admifn - β，可抑制肿瘤生长70%，延长荷瘤小鼠的生存期。有趣的是，这种adifn -b治疗并没有改变诱导型一氧化氮合酶（iNOS）缺失的C57BL/6小鼠的肿瘤生长。免疫组织化学分析显示，AdmIFN-b治疗野生型C57BL/6小鼠肿瘤，导致iNOS表达增加，微血管密度降低，细胞增殖减少，凋亡增加。此外，定量逆转录PCR分析显示，在C57BL/6中，而非iNOS-null对照物中，adifn - β治疗可降低血管生成素、碱性成纤维细胞生长因子、基质金属蛋白酶-9、转化生长因子- β 1、血管内皮生长因子(VEGF)-A和VEGF- b以及抗凋亡分子内皮素-1的mrna水平。这些数据表明，IFN-b基因治疗可能是局部晚期前列腺癌治疗的有效替代方案，并提示NO在体内ifn - β抗肿瘤作用中的强制性作用。
We have previously reported that adenoviral vector-mediated interferon (IFN)-beta gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN-beta (AdmIFN-beta), but not AdE/1 ( a control adenoviral vector), produced approximately 60 ng/10(5) cells/24 h of IFN-beta. The tumorigenicity of AdmIFN-beta-transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 x 10(9) PFU (plaque-forming unit) of AdmIFN-beta inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN-b therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN-b in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-beta therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-beta 1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-b gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-beta antitumoral effects in vivo.