Journal of the National Cancer Institute, 2009, Vol. 101(22), pp.1562-1574
Background Restoring p53 function by antagonizing its interaction with the negative regulator MDM2 is an appealing nongenotoxic approach to treating tumors with wild-type p53. Mutational inactivation of p53 is rare in neuroblastoma tumors at diagnosis and occurs in only a subset of multidrug-resistant neuroblastomas. Methods The antiproliferative and cytotoxic effect of nutlin-3, a small-molecule MDM2 antagonist, was examined in chemosensitive (UKF-NB-3) and matched chemoresistant neuroblastoma cells with wild-type p53 (UKF-NB-3r[DOX.sup.20]) or with mutant p53 (UKF-NB-[3.sup.r][VCR.sup.10]). Activation of the p53 pathway was assessed by expression analysis of p53 target genes, flow cytometric cell cycle analysis, and apoptosis assays. Mice with established chemoresistant tumor xenografts were treated orally with nutlin-3 or vehicle control (n = 5-10 mice per group) and were used to evaluate effects on tumor growth, p53 pathway activity, and metastatic tumor burden. All statistical tests were two-sided. Results Nutlin-3 induced a similar activation of the p53 pathway in UKF-NB-3 and UKF-NB-[3.sup.r][DOX.sup.20] cells, as evidenced by increased expression of p53 target genes, [G.sub.1] cell cycle arrest, and induction of apoptosis. No such response was observed in UKF-NB-[3.sup.r][VCR.sup.10] cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-[3.sup.r][DOX.sup.20] xenograft-bearing mice led to inhibition of primary tumor growth (mean tumor volume after 3 weeks of treatment, nutlin-3-vs vehicle-treated mice: 772 vs 1661 [mm.sup.3], difference = 890 [mm.sup.3], 95% confidence interval = 469 to 1311 [mm.sup.3], P 〈 .001), p53 pathway activation, and reduction in the extent of metastatic disease. The growth of UKF-NB-[3.sup.r][VCR.sup.10] xenografts was unaffected by nutlin-3. Conclusions Nutlin-3 activates the p53 pathway and suppresses tumor growth in this model system of chemoresistant neuroblastoma, provided that wild-type p53 is present. J Natl Cancer Inst 2009;101:1562-1574 DOI: 10.1093/jnci/djp355 [C] The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com. Advance Access publication on November 10, 2009.
Antineoplastic Agents -- Dosage And Administration ; Antineoplastic Agents -- Genetic Aspects ; Neuroblastoma -- Genetic Aspects ; Neuroblastoma -- Drug Therapy ; Neuroblastoma -- Research ; Tumor Suppressor Genes -- Physiological Aspects;