Christoph R Müller, Heidi M Namløs, Johan Bjerner, Ingrid HG Østensen, Gunnar Sæter, Sigbjørn Smeland, Øyvind S Bruland and Ola Myklebost
Interferons (IFNs) may target cancer cells both through their regulation of the immune response, effect on angiogenesis and through direct effect on cancer cells. Treatment response has been demonstrated in osteosarcoma patients, but tumour resistance to IFN-a is common. Hence, understanding the molecular mechanisms involved in response and resistance is essential for improving therapeutic efficacy. Of five xenografts screened for specific growth delay in response to treatment with unconjugated and PEGylated IFN-a2b, one displayed growth inhibition and tumour shrinkage. Growth inhibition increased on a dosing schedule of PEGylated IFN every third day. Xenografts resistant to PEGylated IFN were similarly resistant to unconjugated IFN. Combination treatment with IFN-a2b and doxorubicin resulted in improved growth control rates. Transcriptional profiling analysis of the one sensitive and two resistant xenografts identified a common set of 79 genes significantly affected by IFN-a2b treatment independent of tumour growth inhibition. All but four of the 79 genes were up-regulated. The majority of these genes were well characterized IFN-stimulated genes and core members of the IFN-a signalling pathway. The expression of a set of 128 unique genes changed only in the sensitive xenograft; 52/128 genes were up-regulated. The specific geneexpression pattern seen in the responsive xenograft identified possible pathways important for the antitumor effect of IFN-a in osteosarcoma, including ssubsets of genes involved in cell adhesion and osteogenic tissue development. The observed improved control rates of combined treatment with IFN and doxorubicin are encouraging and should be further explored.
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