Manda T, Shimomura K, Mukumoto S, Kobayashi K, Mizota T, Hirai O, Matsumoto S, Oku T, Nishigaki F, Mori J
Cancer Res. 1987 Jul 15;47(14):3707-11.
The antitumor activity of recombinant human tumor necrosis factor (rTNF-alpha) was examined on murine tumors in mice and in cultured cells in vitro. Mice were implanted intradermally with Meth A fibrosarcoma (Meth A) on day 0. rTNF-alpha caused tumor necrosis and inhibited the tumor growth when given i.v. on day 7 or 10, but not when given on day 3. When rTNF-alpha was given i.v. in doses of 0.1-3.2 micrograms/mouse twice a week for 3 weeks beginning on day 7 or 11, the growth of solid Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, Sarcoma-180, and M5076 reticulum cell sarcoma tumors implanted s.c. or intradermally was markedly inhibited, and the life of the mice bearing these tumors, except M5076 reticulum cell sarcoma, was prolonged. The growth of Meth A implanted i.m. was also markedly inhibited by rTNF-alpha given i.v. However, the life of mice bearing i.p. Colon 26 adenocarcinoma, MH134 hepatoma, Sarcoma-180, and Ehrlich carcinoma was not prolonged by rTNF-alpha given i.p. nine times (days 1-9) in doses up to 1.0 or 3.2 micrograms/mouse. Only in the case of mice bearing i.p. Meth A, the life was slightly prolonged by i.p. treatment with rTNF-alpha but not by i.v. treatment. In experiments against in vitro cultured cells, rTNF-alpha did not show any direct cytotoxicity against mouse tumor cells: Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, and Sarcoma-180, but had a cytotoxic effect against L929 mouse fibroblast. The results suggest that rTNF-alpha is a unique antitumor drug with potent necrotizing activity against solid tumors in mice, and that this activity may derive from indirect mechanisms related to the growth of tumors and not to the direct cytotoxicity of the drug.
在小鼠体内的鼠肿瘤以及体外培养细胞中检测了重组人肿瘤坏死因子（rTNF-α）的抗肿瘤活性。在第0天，将甲基胆蒽A纤维肉瘤（Meth A）皮内植入小鼠体内。当在第7天或第10天静脉注射rTNF-α时，可导致肿瘤坏死并抑制肿瘤生长，但在第3天给药时则无此效果。从第7天或第11天开始，以0.1 - 3.2微克/小鼠的剂量每周静脉注射rTNF-α两次，持续3周，皮下或皮内植入的实体甲基胆蒽A、结肠26腺癌、结肠38癌、肉瘤-180和M5076网状细胞肉瘤肿瘤的生长受到显著抑制，且除M5076网状细胞肉瘤外，携带这些肿瘤的小鼠寿命延长。静脉注射rTNF-α也显著抑制了肌肉注射的甲基胆蒽A的生长。然而，腹腔注射rTNF-α（第1 - 9天，剂量高达1.0或3.2微克/小鼠，共9次）并未延长携带腹腔内结肠26腺癌、MH134肝癌、肉瘤-180和艾氏癌的小鼠寿命。仅在携带腹腔内甲基胆蒽A的小鼠中，腹腔注射rTNF-α可使寿命稍有延长，但静脉注射则无此效果。在针对体外培养细胞的实验中，rTNF-α对小鼠肿瘤细胞（甲基胆蒽A、结肠26腺癌、结肠38癌和肉瘤-180）未显示任何直接细胞毒性，但对L929小鼠成纤维细胞具有细胞毒性作用。结果表明，rTNF-α是一种独特的抗肿瘤药物，对小鼠实体瘤具有强大的坏死活性，且这种活性可能源自与肿瘤生长相关而非药物直接细胞毒性的间接机制。
