Altered expression of the MYCN oncogene modulates MRP gene expression and response to cytotoxic drugs in neuroblastoma cells

We have recently shown a close correlation between expression of the Multid rug Resistance-associated Protein (MRP) gene and the MYCN oncogene and prov ided evidence that high MRP expression is a powerful independent predictor of poor outcome in neuroblastoma (Norris ct al., New Engl. J, Med., 334, 23 1-238, 1996), The effect of MYCN down-regulation on MRP expression and resp onse to cytotoxic drugs was investigated in NBL-S neuroblastoma cells trans fected with MYCN antisense RNA constructs. Concomitant with,MYCN down-regul ation, the level of MRP expression was decreased in the NBAS-4 and NBAS-5 a ntisense transfectants. These cells demonstrated significantly increased se nsitivity to the high affinity MRP substrates vincristine, doxorubicin, sod ium arsenate and potassium antimony tartrate, but not to the poor MRP subst rates, taxol or cisplatin, Similarly, transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in increased MRP expression and si gnificantly increased resistance specifically to MRP substrates. The result s provide evidence for the MYCN oncogene influencing cytotoxic drug respons e via regulation of MRP gene expression, Our data also provide a link betwe en the malignant and chemoresistant phenotypes of this childhood malignancy .