Multidrug resistance in cancer may arise due to alterations in gene expression. In this study, sublines of drug-resistant multiple myeloma (MM) cells, namely RPMI-8226 and U-266, were examined for their differential oncogene-related gene expression levels and the relations to drug resistance were analyzed. Drug resistance was induced by application of the prednisone or vincristine using stepwise dose increments. XTT cytotoxicity assay was used for determination of resistance levels. Microarray analysis was carried out and the genes up- or downregulated more than two-folds were considered as significantly changed. Different types of oncogenes were altered in different drug-resistant RPMI-8226 and U-266 multiple myeloma sublines. The oncogenes which belong to Ras superfamily, especially Rho family of GTPases, were upregulated in prednisone-resistant MM cell lines whereas they were either downregulated or not changed in vincristine resistance. ETS and NF-kappa B2 are among transcription factors which were downregulated in prednisone-resistant cells. Transforming growth factor beta receptor (TGF beta) was downregulated in prednisone-resistant MM cell lines while it was upregulated in vincristine-resistant cell lines. Different types of interleukin gene expressions were seen to be altered in resistant MM sublines whereas suppressors of cytokine signalling genes such as SOCS2, SOCS4 and WSB2 were all downregulated. In conclusion, it is seen that different drugs can induce totally different pathways leading to resistance in the same cancer cell lines. Every drug resistance should be evaluated separately. These facts must be considered in cancer chemotherapy and reversal of drug resistance. (C) 2012 Elsevier Masson SAS. All rights reserved.