Background: Immunochemotherapy (ICT) with interleukin–2 (IL–2) and interferon–α (IFNα) with a secondary effector (5–fluorouracil, 5 FU) is the only promising treatment for advanced renal cell carcinoma (RCC). With IFNα, besides the activation mechanisms of the immunosystem, a direct antitumor effect on tumor cells is expected. Materials and Methods: NF–kB activity in three permanent cell lines (Hep2, HepG2, HT29) and in primary RCC cell lines was measured after incubation with tumor necrosis factor–α (TNFα), IFNα, IFN–γ, TNFα+IFNα, and IFNγ+TNFα, respectively. NF–kB activity and induction of apoptosis by chemotherapeutic drugs (5FU and doxorubicin) were determined in cells transfected with a constitutively active NF–kB p65 or a dominant negative IkB. Results: NF–kB signaling induced by TNFα is suppressed by IFNα and IFNγ in the permanent cell lines and in the primary RCC tumor cell cultures. In an in vitro ICT model we show that pretreatment of RCC with IL–2 and IFNα leads to a diminished NF–kB response to TNFα. In certain tumors, this correlates with increased susceptibility to investigated chemotherapeutic drugs as shown by annexin stain and cell elimination. Modulation of the cellular NF–kB state by a constitutively active p65 or a dominant negative IkB mimics this effect. The IkB construct leads to the same effects as IL–2/IFNα pretreatment as shown by predominant elimination of the transfected cells from the overall population, while introduction of p65 leads to a partial rescue from the effect of IL–2 and IFNα. The described effect, however, applies only to a selection of primary cell cultures. Conclusions: Besides the immunomodulation effects, treatment of RCC with IL–2/IFNα leads to a proapoptotic state in certain tumors. The relevant mediator seems to be IFNα by suppression of the antiapoptotic effect of NF–kB. These data can provide an experimental base for correlation with real patient outcome after ICT.

Keywords:
Renal cell carcinoma, Interferons, Immunochemotherapy
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