Cytokine-mediated reversal of multidrug resistance

The occurrence of the multidrug resistance phenotype still represents a lim iting factor for successful cancer chemotherapy. Numerous efforts have been made to develop strategies for reversal and/or modulation of this major th erapy obstacle through targeting at different levels of intervention. The p henomenon of MDR is often associated with overexpression of resistance-asso ciated genes. Since the classical type of MDR in human cancers is mainly me diated by the P-glycoprotein encoded by the multidrug resistance gene 1, md r1, the majority of reversal approaches target the expression and/or functi on of the mdr1 gene/P-glycoprotein. Due to the fact that the multidrug phen otype always represents the net effect of a panel of resistance-associated genes/gene products, other resistance genes, e.g. those encoding the multid rug resistance-associated protein MRP or the lung resistance protein LRP, w ere included in the studies. Cytokines such as tumor necrosis factor ct and interleukin-2 have been shown to modulate the MDR phenotype in different e xperimental settings in vitro and in vivo. Several studies have been perfor med to evaluate their potential as chemosensitizers of tumor cells in the c ontext of a combined application of MDR-associated anticancer drugs like do xorubicin and vincristine with cytokines. Moreover, the capability of cytok ines to modulate the expression of MDR-associated genes was demonstrated, e ither by external addition or by transduction of the respective cytokine ge ne. Knowledge of the combination effects of cytokines and cytostatics and i ts link to their MDR-modulating capacity may contribute to a more efficient and to a more individualized immuno-chemotherapy of human malignancies.