BIRICODAR (VX-710; Incel (TM)): an effective chemosensitizer in neuroblastoma

Clinical studies have suggested that both MDR1 and MRP may play a significa nt role in the chemosensitivity and outcome of neuroblastoma. To clarify th e nature of multidrug resistance (MDR) in this tumour a series of six neuro blastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MR P, LRP and topoisomerase II genes using reverse transcription polymerase ch ain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed L RP and four expressed MDR1, but protein levels of each of these were variab le. Chemosensitization to a range of MDR-associated drugs (vincristine, dox orubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cis platin, melphalan) by three modulating agents, cyclosporin A, PSG 833 and t he novel Biricodar (VX-710; Incel(TM)), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agent s was evaluated using FAGS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked se nsitization to vincristine was observed in MDR1-positive lines, and a simil ar but less consistent effect was seen with taxotere, doxorubicin and etopo side. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory f actors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.