We have previously shown that ectopic overexpression of retinoic acid receptor (RAR) subtypes a, b and g in human neuroblastoma cells had di erent e ects on growth and retinoid sensitivity. Only overexpressed RARb induced profound growth inhibition in the absence of additional retinoid, and increased retinoid sensitivity. In this study, we measured mRNA expression levels of RARa, b, and g in 50 primary neuroblastoma tumor samples, and found a strong correlation between favorable patient prognosis and high-level RARb expression. Human neuroblastoma cells transfected with a vector expressing RARb demonstrated irreversible growth arrest following a 1 week exposure to all-transretinoic acid, whereas control cells continued to proliferate. In the absence of additional retinoid, RARb transfectants demonstrated a higher proportion of cells in the G 0 /G 1 phase of the cell cycle, increased p21 WAF1/CIP1 expression and speci®c binding to a retinoic acid response element. These were changes which we also observed in control neuroblastoma cells following retinoid treatment. Our data indicate that RARb is an important factor mediating the growth inhibitory e ects of retinoids in neuroblastoma cells. The favorable e ect of high-level RARb expression on prognosis in primary tumor tissue may occur through RARb e ects on p21 expression and consequent G 0 /G 1 cell cycle arrest.

We have previously reported a strong correlation between poor prognosis in childhood neuroblastoma (NB) patients and high-level expression of the transmembrane efflux pump, Multidrug Resistance-associated Protein (MRP1), in NB tumour tissue. In this study, we inhibited the endogenous expression of MRP1 in 2 different NB tumour cell lines by stably transfecting an MRP1 antisense expression vector (MRP-AS). Compared with control cells, MRP-AS transfectant cells demonstrated a higher proportion of dead and morphologically apoptotic cells, spontaneous neuritogenesis, and, increased synaptophysin and neurofilament expression. Bcl-2 protein expression was markedly reduced in MRP-AS cells compared to controls. Conversely, we found that the same NB tumour cell line overexpressing the full-length MRP1 cDNA in sense orientation (MRP-S) demonstrated resistance to the neuritogenic effect of the differentiating agent, all-trans-retinoic acid. Taken together, the results suggest that the level of MRP1 expression in NB tumour cells may influence the capacity of NB cells for spontaneous regression in vivo through cell differentiation and death. © 2001 Cancer Research Campaign  http://www.bjcancer.com

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