CHANGES IN ENDOGENOUS CYTOKINES, ADHESION MOLECULES AND PLATELETS DURING CYTOKINE-INDUCED TUMOR NECROSIS

The aim of this study was to investigate mechanisms of anti-tumour act ivity and necrosis induced by combinations of tumour necrosis factor a lpha (TNF-alpha) and interferon gamma (IFN-gamma). In a breast cancer xenograft model, locally injected recombinant human TNF-alpha arrested growth of established tumours in the absence of overt necrosis. Macro scopic necrosis occurred when rat IFN-gamma, which had no anti-tumour activity as a single agent, was given systemically. Treatment with TNF -alpha and IFN-gamma caused focal engorgement of tumour capillaries wi th erythrocytes, intravascular recruitment of polymorphonuclear cells and platelet adherence to the tumour vascular endothelium 4 h after th e combined treatment. This was followed by destruction of tumour vascu lar endothelium and both necrosis and apoptosis of tumour cells. Conco mitant with these changes, semiquantitative reverse transcriptase-poly merase chain reaction (RT-PCR) analysis revealed the increase of strom al (murine) mRNA levels for TNF-alpha, TNF receptor 55 kDa, TNF recept or 75 kDa, intracellular adhesion molecule 1, vascular cell adhesion m olecule 1, P-selectin and interleukin 6 (IL-6). Thus, the effect of th e combined TNF-alpha and IFN-gamma therapy involved the selective dest ruction of the tumour vasculature, death of tumour cells and increased expression of a series of stromal cytokines, cytokine receptors and a dhesion molecules, which could be implicated in the observed events.