利用肿瘤坏死因子-α（TNF-α）使肿瘤对放射治疗敏感的转化策略。
Translational strategies exploiting TNF-alpha that sensitize tumors to radiation therapy.
作者信息
Mauceri H J, Beckett M A, Liang H, Sutton H G, Pitroda S, Galka E, Efimova E, Darga T, Khodarev N N, King C R, Posner M C, Hellman S, Kufe D W, Weichselbaum R R
机构信息
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
出版信息
Cancer Gene Ther. 2009 Apr;16(4):373-81. doi: 10.1038/cgt.2008.86. Epub 2008 Oct 31.
TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor-alpha (TNF-alpha) (Ad.Egr-TNF) currently in a phase III trial for inoperable pancreatic cancer. We studied B16-F1 melanoma tumors in TNF receptor wild-type (C57BL/6) and deficient (TNFR1,2-/- and TNFR1-/-) mice. Ad.Egr-TNF+IR inhibited tumor growth compared with IR in C57BL/6 but not in receptor-deficient mice. Tumors resistant to TNF-alpha were also sensitive to Ad.Egr-TNF+IR in C57BL/6 mice. Ad.Egr-TNF+IR produced an increase in tumor-associated endothelial cell apoptosis not observed in receptor-deficient animals. Also, B16-F1 tumors in mice with germline deletions of TNFR1,2, TNFR1 or TNF-alpha, or in mice receiving anti-TNF-alpha exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF-alpha signaling in tumor radiosensitivity.
TNFerade是一种可通过辐射诱导表达肿瘤坏死因子-α（TNF-α）的腺病毒载体（Ad.Egr-TNF），目前正处于针对无法手术的胰腺癌的III期试验阶段。我们研究了TNF受体野生型（C57BL/6）和缺陷型（TNFR1,2-/-和TNFR1-/-）小鼠体内的B16-F1黑色素瘤肿瘤。与C57BL/6小鼠单纯接受辐射相比，Ad.Egr-TNF联合辐射抑制了肿瘤生长，但在受体缺陷型小鼠中未出现这种情况。对TNF-α耐药的肿瘤在C57BL/6小鼠中对Ad.Egr-TNF联合辐射也敏感。Ad.Egr-TNF联合辐射使肿瘤相关内皮细胞凋亡增加，而在受体缺陷型动物中未观察到这种情况。此外，TNFR1,2、TNFR1或TNF-α基因缺失的小鼠，或接受抗TNF-α治疗的小鼠体内的B16-F1肿瘤均表现出放射敏感性。这些结果表明，肿瘤相关内皮是Ad.Egr-TNF放射增敏的主要靶点，并表明TNF-α信号传导与肿瘤放射敏感性有关。
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