HUMAN-MELANOMA CELL-LINES SELECTED IN-VITRO DISPLAYING VARIOUS LEVELSOF DRUG-RESISTANCE AGAINST CISPLATIN, FOTEMUSTINE, VINDESINE OR ETOPOSIDE - MODULATION OF PROTOONCOGENE EXPRESSION

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms, involved are largely unknown. In order to establish a repr oducable model system for studying the exact mechanisms conferring che moresistance, we selected drug-resistant sublines in vitro derived fro m one parental human melanoma (MeWo) cell line. Four commonly used che motherapeutic drugs (vindesine, etoposide, fotemustine, cisplatin) wit h different modes of action were choosen and stable sublines exhibitin g foul different levels of resistance against each drug were selected by continuous exposure over two yeats. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-res istance pattern revealed an up to 26-fold increased relative resistanc e against the alkylating agent fotemustine (MeWo(FOTE)) and an up to 3 5.7-fold increased relative resistance against topoisomerase-II-inhibi ting etoposide (MeWo(ETO)) Cisplatin selection (MeWo(CIS)) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas v indesine exposure (MeWo(VIND)) increased relative resistance up to 10. 2-fold. Sublines selected separately for resistance to the DNA-damagin g agents fotemustine, cisplatin and etoposide demonstrated strong cros s-resistance. In comparison to the parental cell line drug-resistant s ublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposi de and fotemustine. Expression of bcl-2 family members (bax, bcl-x) wa s modulated by fotemustine, etoposide and cisplatin. In addition the e xpression of members of the fos (c-fos) and jun (c-jun, jun-D) gene fa mily encoding transcription factors of the AP-1 complex was altered in all drug-resistant sublines. The pattern of expression varied with th e inducing stimulus and this was paralleled by changes in the transact ivation potential of AP-1. Our results reinforce the central role of A P-1 in drug resistance probably through its participation in a program med cellular stress response.