MULTIDRUG-RESISTANCE MODULATION IN RHABDOMYOSARCOMA AND NEUROBLASTOMACELL-LINES

Four rhabdomyosarcoma and three neuroblastoma cell lines were characte rised for the presence of P-glycoprotein and MDR-1 expression using im munohistochemistry, Northern analysis, RT-PCR and in situ mRNA hybridi sation. None of the rhabdomyosarcoma lines were unequivocally positive in contrast to all three neuroblastoma lines. Chemosensitivity to cyt otoxic agents was determined using the MTT assay and chemosensitisatio n by cyclosporin and verapamil was evaluated. In a single rhabdomyosar coma line (HX 170) there was sensitisation to etoposide using verapami l but not to other drugs or using cyclosporin A. In contrast, in all t hree neuroblastoma lines both cyclosporin and verapamil sensitised to vincristine and doxorubicin. No evidence of sensitisation to etoposide was apparent. The sensitisation was most marked for vincristine, usin g either modulator and therefore the influence of modulator scheduling was evaluated with this drug in the neuroblastoma line SK N BE. Prolo nged pre-exposure to modulator did not appear necessary and maximum se nsitisation was apparent where either cyclosporin or verapamil was add ed 1-3 h prior to and post vincristine. Continuity of exposure was imp ortant and even a break of 30 min appeared to reduce sensitisation. Th ese data confirm the potential for chemosensitisation in MDR-1 positiv e neuroblastoma cell lines and provide some basis for rational schedul e design in clinical practice. Because of the probability that vincris tine resistance is predominantly related to MDR-1 and less multifactor ial than for other drugs such as doxorubicin or etoposide, this agent should be considered for inclusion in any clinical evaluation of MDR r eversal strategies.