McIntosh J K, Mulé J J, Travis W D, Rosenberg S A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1990 Apr 15;50(8):2463-9.
The acute hemorrhagic necrosis of tumor nodules caused by the systemic administration of recombinant human tumor necrosis factor alpha (rhTNF-alpha) has been partially attributed to changes in tumor neovascularity. In this study, the effects of rhTNF-alpha were tested on primary autochthonous sarcomas induced in C57BL/6 mice by 3-methylcholanthrene, on spontaneous mammary tumors in C3H/HEN mammary tumor virus positive mice, and on the rejection of normal tissue transplants at different stages of maturity in C57BL/6 mice. Primary i.m. tumors induced by injection of 3-methylcholanthrene grew slowly over a 3-month period and became acutely necrotic after i.v. injection of rhTNF-alpha (2-6 micrograms). In addition, rhTNF-alpha caused a reduction in tumor area of 24% over 10 days compared to a 43% increase in tumor area in control mice receiving excipient (P2 less than 0.01). Histopathologically, tumors underwent central necrosis with a neutrophilic infiltration as was observed previously for serially transplanted tumors following rhTNF-alpha administration. Spontaneous, virally induced mammary tumors underwent a 11% regression on administration of rhTNF-alpha (4-6 micrograms) compared to a 24% growth in mice receiving excipient (P2 less than 0.05). Normal mice were grafted with syngeneic (C57BL/6) or partially allogeneic (C57BL/10 to C57BL/6) skin and were treated with a single dose of rhTNF-alpha (5-20 micrograms) i.v. at either 5, 10, or 15 days posttransplantation. rhTNF-alpha administration had no effect on the integrity of the skin grafts at any maturation point tested (syngeneic graft survival at 60 days: excipient, 35 of 36 versus 20 micrograms rhTNF-alpha, 35 of 36; allogeneic graft survival: excipient, 46 +/- 8 days versus 20 micrograms rhTNF-alpha, 48 +/- 10 days). In addition, rhTNF-alpha had no effect on the integrity of a syngeneic neonatal s.c. heart graft (graft survival at 60 days, excipient, 35 of 36 versus rhTNF-alpha, 30 of 33). Thus, although rhTNF-alpha administration led to marked necrosis and growth inhibition of vascularized tumor, no effect was observed on vascularized normal tissue transplants. To evaluate possible systemic effects of the tumor bearing state on the maturing neovascularity of normal tissue grafts, the three transplant models were studied in mice bearing a 9-day established MCA-106 s.c. sarcoma. After treatment with rhTNF-alpha (2-6 micrograms), acute necrosis and tumor size reduction was apparent in the s.c. tumors; however, no effect was seen in any of the normal tissue transplants.(ABSTRACT TRUNCATED AT 400 WORDS)
全身给予重组人肿瘤坏死因子α（rhTNF-α）导致肿瘤结节急性出血性坏死，部分原因被认为是肿瘤新生血管的改变。在本研究中，检测了rhTNF-α对3-甲基胆蒽诱导的C57BL/6小鼠原发性原位肉瘤、C3H/HEN乳腺肿瘤病毒阳性小鼠的自发性乳腺肿瘤以及C57BL/6小鼠不同成熟阶段正常组织移植排斥反应的影响。经注射3-甲基胆蒽诱导的原发性肌内肿瘤在3个月内生长缓慢，静脉注射rhTNF-α（2 - 6微克）后发生急性坏死。此外，与接受赋形剂的对照小鼠肿瘤面积增加43%相比，rhTNF-α在10天内使肿瘤面积减少了24%（P2＜0.01）。组织病理学上，肿瘤发生中央坏死并伴有中性粒细胞浸润，这与之前rhTNF-α给药后连续移植的肿瘤情况一致。给予rhTNF-α（4 - 6微克）后，自发性病毒诱导的乳腺肿瘤消退了11%，而接受赋形剂的小鼠肿瘤生长了24%（P2＜0.05）。正常小鼠移植同基因（C57BL/6）或部分异基因（C57BL/10至C57BL/6）皮肤，并在移植后5、10或15天静脉注射单剂量rhTNF-α（5 - 20微克）。在任何测试的成熟阶段，rhTNF-α给药对皮肤移植的完整性均无影响（同基因移植60天存活情况：赋形剂组，36只中有35只存活；20微克rhTNF-α组，36只中有35只存活；异基因移植存活情况：赋形剂组，46±8天；20微克rhTNF-α组，48±10天）。此外，rhTNF-α对同基因新生皮下心脏移植的完整性也无影响（60天移植存活情况，赋形剂组，36只中有35只存活；rhTNF-α组，33只中有30只存活）。因此，尽管给予rhTNF-α导致血管化肿瘤明显坏死和生长抑制，但对血管化正常组织移植未见影响。为评估荷瘤状态对正常组织移植成熟新生血管的可能全身影响，在荷9天龄已建立的MCA - 106皮下肉瘤的小鼠中研究了这三种移植模型。用rhTNF-α（2 - 6微克）治疗后，皮下肿瘤出现急性坏死且肿瘤大小减小；然而，在任何正常组织移植中均未见影响。（摘要截短至400字）
