Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a.

Abstract

Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short- and long-term side effects without risking mortality because of tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, Nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, Nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of Nutlin-3a, Nutlin-3a(OC), and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here, we show that Nutlin-3a(OC) specifically and efficiently targets the p53 pathway and that the combination of Nutlin-3a(OC) with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.

• Authors: Rachel C Brennan, Sara Federico, Cori Bradley, Jiakun Zhang, Jacqueline Flores-Otero, Matthew Wilson, Clinton Stewart, Fangyi Zhu, Kip Guy, Michael A Dyer
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 12 Pg. 4205-13 (Jun 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21515735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Piperazines
• Tumor Suppressor Protein p53
• nutlin 3
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Conjunctiva
• Disease Models, Animal
• Humans
• Imidazoles (administration & dosage, chemistry, pharmacokinetics, toxicity)
• Intraocular Pressure (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Piperazines (administration & dosage, chemistry, pharmacokinetics, toxicity)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• Retinal Neoplasms (drug therapy, pathology)
• Retinoblastoma (drug therapy, pathology)
• Solubility
• Tumor Suppressor Protein p53 (physiology)
• Xenograft Model Antitumor Assays