Therapy of selected human malignancies with interferon-a is widely accepted but often complicated by the emergence of interferon-a resistance. Interferon is a pleiotropic cytokine with antiproliferative, antitumour, antiviral and immunmodulatory effect; it signals through the Jak-STAT signal transduction pathway where signal transducer and activator of transcription 1 plays an important role. Here we report both, a lack of signal transducer and activator of transcription induction in interferon-a resistant renal cell carcinoma cells and signal transducer and activator of transcription 1 reinduction of phorbol 12-myristate 13-acetate-stimulated peripheral blood mononuclear cells supernatant. Preliminary experiments on the identification of the molecules that reinducing signal transducers and activators of transcription 1 indicate that interferon-g may be the responsible candidate cytokine, but several others may be involved as well. This work provides the basis for therapeutic strategies directed at the molecular modulation of interferon-a resistance in human neoplasms. Interferon-a (IFN-a) plays an important role in the treatment of various human malignancies, among them renal cell carcinoma (Dorr, 1993); however, response to IFN-a is often impaired by the development of IFN-resistance (Devita et al, 1989), mechanisms of which are poorly understood.Interferon-a belongs to a group of cytokines with antiviral, antiproliferative, antitumour and immunmodulatory activities (Pestka et al, 1987). Binding of IFN-a to the IFN Type I receptor results in oligomerization of the receptor subunits and subsequent transphosphorylation of receptor-associated Janus-kinases Jak1 and Tyk2; activated Jak1 and Tyk2 subsequently phosphorylate tyrosine residues on the associated receptor chain. Signal transducers and activators of transcription (STAT) 1 and 2 can then bind to the receptor by their SH2 domains which are thereupon tyrosine phosphorylated by the receptor-associated Janus-kinases; thereafter, the STATs are released from the receptor and form STAT1-STAT2-heterodimers which translocate to the nucleus where they bind with p48 to form the interferon stimulated gene factor 3 (ISGF3). ISGF3 binds to the interferon stimulated response element (ISRE) in the promoter of IFN-induced genes resulting in transcription of interferon-stimulated genes (ISG) (Schindler and Darnell, 1995;Haque and Williams, 1998).There is evidence that IFN-a resistance is associated with defective components of the Jak-STAT-Pathway (Pansky et al, 2000) e.g., defective activation of ISGF3 (Xu et al, 1994;Wong et al, 1997), lack of STAT1 expression (Sun et al, 1998) or STAT3 induction (Yang et al, 1998. It has been reported that sequential treatment of interferon resistant cells with retinoic acid or tamoxifen followed by interferon-a up-regulates STAT1 expression and ISGF3 activation, respectively, in cells which do not respond to either single agent (Kolla et al, 1996;Lindner et al, 1997).Here we sought (a) to characterize STAT1 deficiency associated wit...