Mulé J J, Asher A, McIntosh J, Lafreniere R, Shiloni E, Lefor A, Reichert C M, Rosenberg S A
Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
Cancer Immunol Immunother. 1988;26(3):202-8. doi: 10.1007/BF00199930.
We examined the antitumor efficacy of rTNF-alpha administration on established tumor at two visceral sites, lungs and liver. Treatment of B6 mice harboring multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) 10-day pulmonary macrometastases from the MCA-106 sarcoma, with dosages of rTNF-alpha (5-10 micrograms, single dose i.v.) that caused hemorrhagic necrosis and regression of a 6 mm MCA-106 s.c. tumor, had no impact on the number (or size) of lung nodules. Similarly, rTNF-alpha failed to show an antitumor effect in B6 mice with advanced day 8 or 10 multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) hepatic metastases at single i.v. doses up to 20 micrograms, as measured by either enumeration of residual liver nodules or survival. B6 mice injected s.c. with MCA-106 sarcoma and treated with rTNF-alpha as a single i.v. dose on day 0, 3, 5, or 7 experienced marked tumor regression only after the day 7 rTNF-alpha injection, when the tumor had achieved a size of 5-6 mm in diameter. Since tumor size appeared important for rTNF-alpha susceptibility in vivo, we next induced a single hepatic tumor of the MCA-106 sarcoma by the direct injection of cells into the left lobe of the liver and treated these mice at day 10 when the nodule had achieved a size of 5-6 mm in diameter. Increasing doses of rTNF-alpha (up to 8 micrograms) given as a single i.v. injection resulted in increasingly greater reductions in hepatic tumor as well as significant survival benefit of the treated mice. Sites of regressing hepatic tumor exhibited central necrosis accompanied by polymorphonuclear leukocytes and lymphocytes. Collectively, these results show that rTNF-alpha administration can mediate a significant antitumor effect on visceral tumor and suggest that tumor size is an important factor in rTNF-alpha susceptibility not only for tumors growing at s.c. sites but also for those established at visceral sites.
我们研究了静脉注射重组肿瘤坏死因子-α（rTNF-α）对肺和肝这两个内脏部位已形成肿瘤的抗肿瘤效果。用能使直径6mm的MCA-106皮下肿瘤发生出血性坏死并消退的rTNF-α剂量（5-10微克，单次静脉注射），治疗携带来自MCA-106肉瘤的多发性（超过100个直径小于或等于0.5mm的病灶）10天肺大转移灶的B6小鼠，结果对肺结节的数量（或大小）没有影响。同样，对于第8天或第10天患有晚期多发性（超过100个直径小于或等于0.5mm的病灶）肝转移的B6小鼠，静脉注射单次剂量高达20微克的rTNF-α，无论是通过计数残留肝结节还是观察生存率，均未显示出抗肿瘤作用。皮下注射MCA-106肉瘤并在第0、3、5或7天接受单次静脉注射rTNF-α治疗的B6小鼠，仅在第7天注射rTNF-α后（此时肿瘤直径已达5-6mm）才出现明显的肿瘤消退。由于肿瘤大小似乎对体内rTNF-α敏感性很重要，接下来我们通过将细胞直接注射到肝脏左叶诱导产生单个MCA-106肉瘤肝肿瘤，并在第10天结节直径达到5-6mm时对这些小鼠进行治疗。单次静脉注射递增剂量的rTNF-α（高达8微克）导致肝肿瘤的缩小程度越来越大，同时治疗小鼠的生存率也显著提高。消退的肝肿瘤部位表现为中央坏死，并伴有多形核白细胞和淋巴细胞。总体而言，这些结果表明，静脉注射rTNF-α可介导对内脏肿瘤的显著抗肿瘤作用，并提示肿瘤大小不仅是皮下生长肿瘤，也是内脏部位已形成肿瘤对rTNF-α敏感性的一个重要因素。
