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.

Mickisch GH, Roehrich K, Koessig J, Forster S, Tschada RK, Alken PM: Mechanisms and modulation of multidrug resistance in primary renal cell carcinoma. J Urol 1990;144:755– 759.
Harris DT: Hormonal therapy and chemotherapy of renal cell carcinoma. Semin Oncol 1983;10:422–430.
Huguenin PU, Kieser S, Glanzmann C, Capaul R, Lutolf UM: Radiotherapy for metastatic carcinomas of the kidney or melanomas: An analysis using palliative endpoints. Int J Radiat Oncol Biol Phys 1998;41:401–405.
Mickisch GH: Immunotherapy of renal cell carcinoma. Urol Int 1999;63:16–21.
Taneja SS, Pierce W, Figlin R, Belldegrun A: Immunotherapy for renal cell carcinoma: The era of interleukin–2–based treatment. Urology 1995;45:911–924.
Angus R, Collins CM, Symes MO: The effect of alpha and gamma interferon on cell growth and histocompatibility antigen expression by human renal carcinoma cells in vitro. Eur J Cancer 1993;29A:1879–1885.
Grem JL, van Groeningen CJ, Ismail AA, Johnston PG, Alexander HR, Allegra CJ: The role of interferon alpha as a modulator of fluorouracil and leucoverin. Eur J Cancer 1995; 31A:1316–1320.
Szabo G, Mandrekar P, Bellarose G, Catalano D: IFNalpha and ethanol augment NF–kB in HepG2 cells and monocyte IL–12, TNFalpha, and IL–6 production. Hepatology 1999;30: (suppl):374.
Gaweco AS, Kania RJ, Friedlander L, Mtchell B, Cross P, Molloy PJ, Van Thiel DH: Disappearence of hepatitis C virus in the liver after IFN–treatment is associated with downregulated NF–kB activation and IL–6 expression. Hepatology 1997;26(suppl):309.
Beg AA, Baltimore D: An essential role of NF–kB in preventing TNFalpha–induced cell death. Science 1996;274:782–784.
Wang CY, Mayo MW, Baldwin AS Jr: TNF– and cancer therapy–induced apoptosis: Potentiation by inhibition of NF–kB. Science 1996; 274:784–787.
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM: Suppression of TNFalpha–induced apoptosis by NF–kB. Science 1996;274: 787–789.
Lopez Collazo E, Hortelano S, Rojas A, Bosca L: Triggering of peritoneal macrophages with IFN alpha/beta attenuates the expression of inducible nitric oxide synthase through a decrease in Nf–kappaB activation. J Immunol 1998;160:2889–2895.
Faure V, Courtois Y, Goureau O: Inhibition of inducible nitric oxide synthase expression by interferons alpha and beta in bovine retinal pigmented epithelial cells. J Biol Chem 1997; 272:32169–32175.
Gribaudo G, Ravaglia S, Gaboli M, Gariglio M, Cavallo R, Landolfo S: Interferon–alpha inhibits the murine cytomegalovirus immediate–early gene expression by downregulating NF–kappa B activity. Virology 1995;211:251–260.
Uzzo RG, Rayman P, Kolenko V, Clark PE, Cathcart MK, Bloom T, Novick AC, Bukowski RM, Hamilton T, Finke JH: Renal cell carcinoma–derived gangliosides suppress nuclear factor–kappaB activation in T cells. J Clin Invest 1999;104:769–776.
Knoefel B, Nuske K, Steiner T, Junker K, Kosmehl H, Rebstock K, Reinhold D, Junker U: Renal cell carcinomas produce IL–6, IL–10, IL–11, and TGF–β1 in primary cultures and modulate lymphocyte blast transformation. J Interferon Cytokine Res 1997;17:95–102.
Cherrington JM, Mocarski ES: Human cytomegalovirus iel transactivates the alpha promoter–enhancer via an 18–base–pair repeat element. J Virol 1989;63:1435–1440.
Perkins ND, Schmid RM, Duckett CS, Leung K, Rice NR, Nabel GJ: Distinct combinations of NF–kB subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci USA 1992;89:1529–1533.
Rice NR, MacKichan ML, Israel A: The precursor of NF–kB p50 has Ikb–like functions. Cell 1992;71:243–253.
Yang CH, Murti A, Pfeffer SR, Kim JG, Donner DB, Pfeffer LM: IFN activates NF–kB to promote cell survival through a pathway involving STAT3, PI–3K and Akt. J Interferon Cytokine Res 1999;19(suppl 1):123.
Oliveira IC, Mukaida N, Matsushima K, Vilcek J: Transcriptional inhibition of interleukin–8 gene by interferons is mediated by the NF–kappa B site. Mol Cell Biol 1994;14:5300– 5308.
Ten RM, Blank V, Le Bail O, Kourilsky P, Israel A: Two factors, IRF1 and KBF1/NF–kappa B, cooperate during induction of MHC class I gene expression by interferon alpha beta or Newcastle disease virus. C R Acad Sci III 1993;316:496–501.
Thomas NS, Pizzey AR, Tiwari S, Williams CD, Yang J: p130, p107, and pRb are differentially regulated in proliferating cells and during cell cycle arrest ba alpha–interferon. J Biol Chem 1998;273:23659–23667.
Murphy D, Farwig K, Detjen K, Welzel M, Riecksen EO, Wiedemann B, Rosewicz S: Molekulare Mechanismen der antiproliferativen Effekte von Interferon alpha in humanen hepatozellulären Karzinomzellen. Z Gastroenterol 1999;37:919.
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