Studies of Effects of Recombinant Human Tumor Necrosis Factor on Autochthonous Tumor and Transplanted Normal Tissue in Mice

Joe K. McIntosh, James J. Mulé, William D. Travis, Steven A. Rosenberg

Research output: Contribution to journalArticlepeer-review

Abstract

The acute hemorrhagic necrosis of tumor nodules caused by the systemic administration of recombinant human tumor necrosis factor a (rhTNF-cr) has been partially attributed to changes in tumor neovascu-larity. In this study, the effects of rhTNF-a were tested on primary autochthonous sarcomas induced in C57BIV6 mice by 3-methylcholan-threne, 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-a (2-6 Mg). In addition, rhTNF-a 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 < 0.01). Histopathologically, tumors underwent central necrosis with a neutrophilic infiltration as was observed previously for serially transplanted tumors following rhTNF-a administration. Spontaneous, virally induced mammary tumors underwent a 11% regression on administration of rhTNF-a (4-6 Mg) compared to a 24% growth in mice receiving excipient (P2 < 0.05). Normal mice were grafted with syngeneic (C57BL/6) or partially aUogeneic (C57BL/10 to C57BL/6) skin and were treated with a single dose of rhTNF-a (5-20 Mg) i.v. at either 5,10, or 15 days posttransplantation. rhTNF-a 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 Mg rhTNF-a, 35 of 36; allogeneic graft survival: excipient, 46 ± 8 days versus 20 Mg rhTNF-a, 48 ± 10 days). In addition, rhTNF-a 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-a, 30 of 33). Thus, although rhTNF-a 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-a (2-6 Mg), 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. We discuss possible mechanisms for the difference in TNF-a sensitivity between normal tissue grafts and tumors as they relate to neovascularity.

Original languageEnglish (US)
Pages (from-to)2463-2469
Number of pages7
JournalCancer Research
Volume50
Issue number8
StatePublished - Apr 15 1990

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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