Paradoxical effects of tumour necrosis factor in experimental ovarian cancer

Abstract

Recombinant human tumour necrosis factor (rhTNF) had anti‐tumour activity against 2 of 3 human ovarian cancer xenografts growing intraperitonealy (i.p.) in nude mice, producing a moderate (2‐ to 3‐fold) increase in mouse survival time. rhTNF therapy caused a marked influx of polymorphonuclear neutrophils into the peritoneal cavity during the first few days of daily therapy. This was accompanied by a decrease in the number of peritoneal macrophages and lymphocytes. rhTNF also caused an increase in peripheral blood neutrophils. With continuation of daily therapy, the peritoneal neutrophil influx diminished, with restoration of the macrophage and lymphocyte populations. After 2 to 3 weeks there was a small but significant increase in peritoneal Thy 1.2 cells. In the peripheral blood, the neutrophilia was less marked than at the start of therapy. Mild myelosuppression was indicated by significant falls in haemoglobin and platelet counts. Within 24 hr of the start of therapy in the 2 responsive xenografts (HU and LA) tumour clumps in the peritoneum were surrounded by host inflammatory cells, and tumours fixed to the omentum were infiltrated by neutrophils and mononuclear cells. In both instances necrosis was evident by 4 to 7 days. The third xenograft (OS) grew although the rhTNF therapy induced the same inflammatory changes in the peritoneum. In contrast to its positive effect on the survival of tumour‐bearing mice, rhTNF promoted the adhesion of tumour cells to the peritoneum and their establishment as tumour nodules below the mesothelial surface. This phenomenon was seen in all 3 xenografts including the OS xenograft which did not respond in any other way to rhTNF therapy.