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Previous Volume 334:231-238 January 25, 1996 Number 4 Next

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ABSTRACT

Background Overexpression of the gene for the multidrug-resistance–associated protein (MRP) has been linked with resistance to chemotherapeutic agents (multidrug resistance) in vitro. The expression of MRP by neuroblastoma cells correlates with N-myc oncogene amplification, a well-established prognostic indicator in patients with neuroblastoma.

Methods To relate MRP gene expression to established prognostic markers and the clinical outcome of neuroblastoma, we analyzed MRP expression in specimens of primary tumors from 60 patients with neuroblastoma.

Results Levels of MRP gene expression were significantly higher in tumors with N-myc amplification than in tumors without such amplification (P<0.001). High levels of MRP expression were strongly associated with reductions in both survival and event-free survival (P<0.001) in the overall study population and in subgroups of patients without N-myc amplification and patients with localized disease. For the overall study population, the five-year cumulative survival rates in the groups with high and low levels of MRP expression were 57 percent (95 percent confidence interval, 37 to 78 percent) and 94 percent (95 percent confidence interval, 86 to 100 percent), respectively. In contrast, expression of the MDR1 multidrug-resistance gene was not predictive of survival or event-free survival. After adjustment by multivariate analysis for the effects of N-myc amplification and other prognostic indicators, high levels of MRP expression retained significant prognostic value for poor survival (relative hazard, 14.9; P = 0.01) and poor event-free survival (relative hazard, 9.7; P = 0.004), whereas N-myc amplification had no prognostic value.

Conclusions High levels of MRP gene expression in patients with neuroblastoma correlate strongly with poor outcome. The findings suggest that expression of this multidrug-resistance gene accounts for the association between N-myc amplification and reduced survival.

Source Information

From the Children's Leukaemia and Cancer Research Centre, University of New South Wales and Prince of Wales Children's Hospital, Sydney, Australia (M.D.N., S.B.B., G.M.M., M.H.); the Department of Gastroenterology, Prince of Wales Hospital, Sydney, Australia (P.S.H.); and the Department of Pediatrics, Northwestern University Medical School and Children's Memorial Hospital, Chicago (S.L.C.).

Address reprint requests to Dr. Michelle Haber at the Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, NSW 2031, Australia.

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• Raggi, C. C., Bagnoni, M. L., Tonini, G. P., Maggi, M., Vona, G., Pinzani, P., Mazzocco, K., De Bernardi, B., Pazzagli, M., Orlando, C. (1999). Real-Time Quantitative PCR for the Measurement of MYCN Amplification in Human Neuroblastoma with the TaqMan Detection System. Clin. Chem. 45: 1918-1924 [Abstract] [Full Text]  
• Glick, R. D., Swendeman, S. L., Coffey, D. C., Rifkind, R. A., Marks, P. A., Richon, V. M., La Quaglia, M. P. (1999). Hybrid Polar Histone Deacetylase Inhibitor Induces Apoptosis and CD95/CD95 Ligand Expression in Human Neuroblastoma. Cancer Res. 59: 4392-4399 [Abstract] [Full Text]  
• Maris, J. M., Matthay, K. K. (1999). Molecular Biology of Neuroblastoma. JCO 17: 2264-2264 [Abstract] [Full Text]  
• Gilbert, J., Haber, M., Bordow, S. B., Marshall, G. M., Norris, M. D. (1999). Use of Tumor-Specific Gene Expression for the Differential Diagnosis of Neuroblastoma from Other Pediatric Small Round-Cell Malignancies. Am. J. Pathol. 155: 17-21 [Abstract] [Full Text]  
• Huhn, S. L., Mohapatra, G., Bollen, A., Lamborn, K., Prados, M. D., Feuerstein, B. G. (1999). Chromosomal Abnormalities in Glioblastoma Multiforme by Comparative Genomic Hybridization: Correlation with Radiation Treatment Outcome. Clin. Cancer Res. 5: 1435-1443 [Abstract] [Full Text]  
• Dwivedi, R. S., Wang, L.-J., Mirkin, B. L. (1999). S-Adenosylmethionine Synthetase Is Overexpressed in Murine Neuroblastoma Cells Resistant to Nucleoside Analogue Inhibitors of S-Adenosylhomocysteine Hydrolase: A Novel Mechanism of Drug Resistance. Cancer Res. 59: 1852-1856 [Abstract] [Full Text]  
• Young, L. C., Campling, B. G., Voskoglou-Nomikos, T., Cole, S. P. C., Deeley, R. G., Gerlach, J. H. (1999). Expression of Multidrug Resistance Protein-related Genes in Lung Cancer: Correlation with Drug Response. Clin. Cancer Res. 5: 673-680 [Abstract] [Full Text]  
• Roelofsen, H, Hooiveld, G., Koning, H, Havinga, R, Jansen, P., Muller, M (1999). Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein. J. Cell Sci. 112: 1395-1404 [Abstract]  
• Toth, K., Vaughan, M. M., Schwartz, G., Winston, J. S., Skenderis, B. S. II, Slocum, H. K., Rustum, Y. M. (1998). Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections. INT J SURG PATHOL 6: 145-154 [Abstract]  
• den Boer, M.L., Pieters, R., Kazemier, K.M., Rottier, M.M.A., Zwaan, C.M., Kaspers, G.J.L., Janka-Schaub, G., Henze, G., Creutzig, U., Scheper, R.J., Veerman, A.J.P. (1998). Relationship Between Major Vault Protein/Lung Resistance Protein, Multidrug Resistance-Associated Protein, P-Glycoprotein Expression, and Drug Resistance in Childhood Leukemia. Blood 91: 2092-2098 [Abstract] [Full Text]  
• Zhan, Z., Sandor, V. A., Gamelin, E., Regis, J., Dickstein, B., Wilson, W., Fojo, A. T., Bates, S. E. (1997). Expression of the Multidrug Resistance-Associated Protein Gene in Refractory Lymphoma: Quantitation by a Validated Polymerase Chain Reaction Assay. Blood 89: 3795-3800 [Abstract] [Full Text]  
• Duhem, C., Ries, F., Dicato, M. (1996). What does Multidrug Resistance (MDR) Expression Mean in the Clinic?. The Oncologist 1: 151-158 [Abstract] [Full Text]  
• Rosenberg, M. F., Mao, Q., Holzenburg, A., Ford, R. C., Deeley, R. G., Cole, S. P. C. (2001). The Structure of the Multidrug Resistance Protein 1 (MRP1/ABCC1). CRYSTALLIZATION AND SINGLE-PARTICLE ANALYSIS. J. Biol. Chem. 276: 16076-16082 [Abstract] [Full Text]