Expression of the MDR1 gene product P-glycoprotein in childhood neuroblastoma

Abstract

BACKGROUND. In cancer treated with chemotherapy, multidrug resistance is characterized by increased genetic expression of P-glycoprotein (P-gp), which acts as an ATP-dependent drug-efflux pump. However, the clinical significance of the expression of the multidrug resistance gene (MDR1) product P-gp in neuroblastoma (NB) is still a matter of debate. In this study, the role of the expression of P-gp in NB was evaluated. METHODS. NB tumor imprints and NB positive bone marrow smears from 23 children before and after multidrug chemotherapy were examined for P-gp expression by antialkaline phosphatase immunocytochemical analysis. RESULTS. Before chemotherapy, only 10% of the NB samples showed positivity for P-gp. At diagnosis, no difference in P-gp expression was found between primary tumor cells and NB cells from metastases to bone marrow. P-gp positivity was only observed in patients with nonlocalized disease. P-gp positivity was never found in tumor cells that were histologically well differentiated. No clear correlation of P-gp positivity with poor prognostic parameters, such as chromosome 1p deletion or MYCN amplification, were found. Multidrug chemotherapy did not induce enhanced expression of P-gp in the neuroblasts. However, at clinical recurrence, P-gp expression was found in the metastatic NB cells of five of seven bone marrow samples examined. CONCLUSIONS. The prognostic relevance of P-gp expression in NB was not clear from the results of this study. To resolve the uncertainties, a standardization of the methodology and more prospective studies are needed to determine whether routine analysis of P-gp is worth adding to the other prognostic parameters that are evaluated in NB patients. The finding that metastatic cells are capable of expressing MDR1, in contrast to the NB cells of the primary tumor, would certainly be an interesting topic for further study as work directed at understanding the progression to metastasis continues.