Palladino M A, Shalaby M R, Kramer S M, Ferraiolo B L, Baughman R A, Deleo A B, Crase D, Marafino B, Aggarwal B B, Figari I S
J Immunol. 1987 Jun 1;138(11):4023-32.
We have investigated the in vitro and in vivo antitumor activities of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) against Meth A sarcoma. Meth A sarcoma cells were found to a) be relatively insensitive in vitro to rHuTNF-alpha, and b) express low numbers of TNF-alpha receptors. Intraperitoneally implanted Meth A sarcoma was insensitive to the antitumor effects of rHuTNF-alpha. In contrast, rHuTNF-alpha was highly efficacious against subcutaneously implanted Meth A sarcoma. Biodistribution studies with 125I- or 3H-labeled rHuTNF-alpha demonstrated that, after intravenous administration, the majority of the labeled rHuTNF-alpha localized in the kidney, lungs, and liver. Only low levels of radiolabel were found in subcutaneous Meth A implants. These results support the in vitro data on the low number of TNF-alpha receptors on Meth A sarcoma cells. The ability of rHuTNF-alpha to induce regression of established (7 days) subcutaneous Meth A implants, positively correlated with the degree of both macroscopic and microscopic tumor necrosis. In addition, recombinant human tumor necrosis factor-beta (lymphotoxin) and recombinant murine tumor necrosis factor-alpha induced similar levels of necrosis. Other lymphokines with known antitumor activities, recombinant human interferon-gamma, murine interferon-gamma, and human interleukin 1 alpha, failed to induce detectable necrosis of Meth A sarcoma. Mice which had rejected subcutaneous Meth A sarcoma implants after rHuTNF-alpha treatment and which were later challenged subcutaneously with Meth A sarcoma or other noncross-reacting chemically induced sarcomas were found to be specifically immune to Meth A sarcoma. In addition, low levels of cytotoxic antibodies reactive to Meth A sarcoma were detected in the sera of 21 of 30 Meth A immune mice. Histological evaluation of the hemorrhagic tumor necrosis induced by rHuTNF-alpha suggests that the primary lesion is vascular, possibly directly on the endothelial cells. The mechanisms involved in the generation of specific cell-mediated antitumor immunity in this model are at present unknown.
我们研究了重组人肿瘤坏死因子-α（rHuTNF-α）对Meth A肉瘤的体内外抗肿瘤活性。发现Meth A肉瘤细胞：a）在体外对rHuTNF-α相对不敏感；b）表达少量的TNF-α受体。腹腔内植入的Meth A肉瘤对rHuTNF-α的抗肿瘤作用不敏感。相反，rHuTNF-α对皮下植入的Meth A肉瘤具有高效作用。用125I或3H标记的rHuTNF-α进行的生物分布研究表明，静脉注射后，大部分标记的rHuTNF-α定位于肾脏、肺和肝脏。在皮下Meth A植入物中仅发现低水平的放射性标记。这些结果支持了关于Meth A肉瘤细胞上TNF-α受体数量少的体外数据。rHuTNF-α诱导已建立（7天）的皮下Meth A植入物消退的能力，与宏观和微观肿瘤坏死程度呈正相关。此外，重组人肿瘤坏死因子-β（淋巴毒素）和重组鼠肿瘤坏死因子-α诱导了相似程度的坏死。其他具有已知抗肿瘤活性的淋巴因子，重组人干扰素-γ、鼠干扰素-γ和人白细胞介素1α，未能诱导Meth A肉瘤出现可检测到的坏死。在用rHuTNF-α治疗后排斥皮下Meth A肉瘤植入物且随后皮下接种Meth A肉瘤或其他非交叉反应性化学诱导肉瘤的小鼠中，发现它们对Meth A肉瘤具有特异性免疫。此外，在30只Meth A免疫小鼠中的21只血清中检测到了对Meth A肉瘤有反应的低水平细胞毒性抗体。对rHuTNF-α诱导的出血性肿瘤坏死的组织学评估表明，主要病变是血管性的，可能直接作用于内皮细胞。目前尚不清楚该模型中特异性细胞介导的抗肿瘤免疫产生所涉及的机制。
