Effects of tumour necrosis factor on human tumour xenografts in nude mice.

Abstract

Recombinant human tumour necrosis factor (rHuTNF) when injected intraperitoneally into nude mice bearing subcutaneous tumour xenografts (breast and bowel) had no significant antitumour activity (six different tumours were tested). The same dose administered locally at the tumour site resulted in complete regression and cure of the majority of tumours. Macroscopic evidence of tumour necrosis was rarely seen but microscopically a peritumoral cuff of host inflammatory cells surrounded the dying tumour cells within four days of the start of therapy. The combination of rHuTNF (i.p.) with recombinant human gamma-interferon (rHuIFN-gamma) (i.p.) led to significant tumour inhibition in only one of three xenografts tested. Combination of rHuTNF (i.p.) and HuIFN-alpha (s.c.) resulted in significant inhibition in all of three xenografts tested. Human ovarian tumours were grown in the peritoneal cavity of nude mice. The biological behaviour of this cancer closely resembled the human disease, the xenografts growing as solid tumours and/or ascites. When rHuTNF or rHuIFN-gamma were given intraperitoneally at the time of tumour cell injection most mice survived, whereas control mice died in 4-8 weeks. Once the disease was established (seven days or more after injection) either agent alone was ineffective. In the combined results of three experiments with one xenograft, with a total of 21 mice in each group, cumulative survival at 154 days was 0% for control mice and 5% and 15% for mice treated with 1 microgram/day rHuTNF or 5 X 10(4) U/day rHuIFN-gamma, respectively, when therapy was started seven days after tumour cell injection. Combining the two agents led to a cumulative survival of 85%. This combination cured 40% of mice by 21 days after tumour cell injection. With a further two ovarian cancer xenografts, the combination of rHuTNF and rHuIFN-gamma produced a significant survival advantage.