Havell E A, Fiers W, North R J
Trudeau Institute, Saranac Lake, New York 12983.
J Exp Med. 1988 Mar 1;167(3):1067-85. doi: 10.1084/jem.167.3.1067.
The ability of murine recombinant tumor necrosis factor (rTNF) and natural TNF in tumor-necrotizing serum (TNS) to cause regression of the SA1 sarcoma was investigated. We found that to cause regression of a 9-d SA1 sarcoma, near lethal quantities of rTNF and TNS had to be given to the host. However, even at these highly toxic doses, rTNF was not reliable at causing complete tumor regression. On the other hand, both types of TNF were reliable at causing a tumor hemorrhagic reaction that resulted in the destruction of greater than 75% of the tumor's center in 24 h. The TNF-induced hemorrhagic reaction involved the development of numerous petechial hemorrhages in the tumor's vascular bed, which apparently resulted from destruction of the tumor's blood vessels. It was possible to follow the development of the hemorrhagic reaction against time after giving rTNF or TNS by measuring the intratumor extravasation of 51Cr-labeled syngeneic red cells. According to this method, TNF-induced intratumor hemorrhaging was in progress within 1 h of giving TNF and continued for about a 6-h period. However, the hemorrhagic reaction was greatly reduced and complete regression of the rim of the living tumor tissue that survived hemorrhagic necrosis failed to occur, if SA1 sarcoma was growing in T cell-deficient (TXB) mice. This indicates that the TNF-induced hemorrhagic reaction is partly dependent, and the tumor regression that follows is completely dependent on host immunocompetence. This suggests in turn, that rTNF does not directly destroy SA1 tumor cells in vivo, even though it was shown that it can destroy SA1 tumor cells in vitro. This interpretation is supported by the additional findings that rTNF was no more therapeutic against a 3-d (3-mm) SA1 than against a 9-d (8-mm) SA1, and was no more therapeutic when injected directly into the tumor than when injected intravenously. Lastly it was possible to completely inhibit the ability of rTNF and TNS to cause tumor hemorrhagic necrosis and regression by infusing the host with a monospecific, polyvalent anti-rTNF antibody that neutralized the cytotoxic action of rTNF in vitro.
研究了小鼠重组肿瘤坏死因子（rTNF）和肿瘤坏死血清（TNS）中的天然TNF使SA1肉瘤消退的能力。我们发现，要使9日龄的SA1肉瘤消退，必须给宿主注射接近致死量的rTNF和TNS。然而，即使在这些高毒性剂量下，rTNF也不能可靠地导致肿瘤完全消退。另一方面，两种类型的TNF都能可靠地引起肿瘤出血反应，在24小时内导致肿瘤中心超过75%被破坏。TNF诱导的出血反应涉及肿瘤血管床出现大量瘀点性出血，这显然是由于肿瘤血管被破坏所致。通过测量51Cr标记的同基因红细胞在肿瘤内的外渗情况，可以跟踪给予rTNF或TNS后出血反应随时间的发展。根据这种方法，TNF诱导的肿瘤内出血在给予TNF后1小时内开始，并持续约6小时。然而，如果SA1肉瘤在T细胞缺陷（TXB）小鼠中生长，出血反应会大大减少，并且出血性坏死存活的活肿瘤组织边缘未能完全消退。这表明TNF诱导的出血反应部分依赖于宿主免疫能力，随后的肿瘤消退则完全依赖于宿主免疫能力。这反过来表明，rTNF在体内不会直接破坏SA1肿瘤细胞，尽管已证明它在体外可以破坏SA1肿瘤细胞。这一解释得到了其他发现的支持，即rTNF对3日龄（3毫米）的SA1肉瘤的治疗效果并不比对9日龄（8毫米）的SA1肉瘤更好，并且直接注射到肿瘤内时的治疗效果并不比静脉注射时更好。最后，通过给宿主输注一种在体外中和rTNF细胞毒性作用的单特异性多价抗rTNF抗体，可以完全抑制rTNF和TNS引起肿瘤出血坏死和消退的能力。
