Han S K, Brody S L, Crystal R G
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Am J Respir Cell Mol Biol. 1994 Sep;11(3):270-8. doi: 10.1165/ajrcmb.11.3.8086165.
The clinical use of tumor necrosis factor-alpha (TNF) is constrained by tumor cell resistance and systemic toxicity. Based on observations with murine tumors, we hypothesized that induction of local TNF production by the tumor may suppress growth of human cancer cells. To evaluate this, a human TNF cDNA was transferred to human lung cancer cell lines in vitro using a retrovirus vector to produce TNF cDNA-modified cell lines secreting TNF. In vitro cell growth was similar for parental and modified cells. All cells were resistant to TNF. The in vivo tumorigenicity of parental and modified cells was compared in nude mice. Animals injected subcutaneously with parental cells uniformly developed tumors. Tumor growth was markedly less for all modified cells, and this suppression of tumor development was reversed by anti-TNF antibody administration. Animals injected with a mixture of 50% modified and 50% parental cells or parental cell tumors injected with modified cells had decreased tumor growth, demonstrating that modified cells could suppress tumorigenicity. These data suggest that TNF can induce antitumor defenses to suppress in vivo human tumor cell growth and provide a rationale for transferring the human TNF cDNA directly to malignant cells for the therapy of human lung cancer.
肿瘤坏死因子-α（TNF）的临床应用受到肿瘤细胞耐药性和全身毒性的限制。基于对小鼠肿瘤的观察，我们推测肿瘤局部产生TNF可能会抑制人类癌细胞的生长。为了评估这一点，我们使用逆转录病毒载体将人TNF cDNA体外转染至人肺癌细胞系，以产生分泌TNF的TNF cDNA修饰细胞系。亲本细胞和修饰细胞的体外细胞生长情况相似。所有细胞均对TNF耐药。我们在裸鼠中比较了亲本细胞和修饰细胞的体内致瘤性。皮下注射亲本细胞的动物均长出肿瘤。所有修饰细胞的肿瘤生长明显较慢，并且通过给予抗TNF抗体可逆转这种肿瘤发展的抑制作用。注射50%修饰细胞和50%亲本细胞混合物的动物或注射了修饰细胞的亲本细胞肿瘤的动物，其肿瘤生长均减缓，这表明修饰细胞可以抑制致瘤性。这些数据表明，TNF可以诱导抗肿瘤防御反应以抑制体内人类肿瘤细胞的生长，并为将人TNF cDNA直接转染至恶性细胞用于治疗人类肺癌提供了理论依据。
