Inactivation of the p53 pathway in Retinoblastoma

Inactivation of the p53 pathway in retinoblastoma

Vol 444 | 2 November 2006 | doi:10.1038/nature05194

These findings not only challenge the long-standing belief that retinoblastoma is the exception to the rule that the Rb and p53 pathways must be inactivated in cancer, but also provide a specific target
for chemotherapy.

Nutlin-3 antagonizes the MDMX–p53 interaction and efficiently kills retinoblastoma cells. In addition, combining nutlin-3 with topotecan synergistically increases tumour cell killing.

On the basis of our preclinical studies, we propose that subconjunctival administration of these two drugs could achieve the same synergistic effect in individuals with retinoblastoma without causing the side-effects associated with prolonged systemic exposure to broad-spectrum chemotherapeutic drugs. Local delivery of nutlin-3 or other MDMX inhibitors being developed may also be beneficial for the treatment of breast, colon, lung and prostate cancers with MDMX
amplifications.

Dr. Finger notes that this is an "excellent example of multinational cooperation." This study came from researchers from the Department of Developmental Neurobiology, Department of Chemical Biology and Therapeutics, 3Department of Pathology, 4Department of Surgery, Division of Ophthalmology, and Department of Hematology-Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA. Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California 94143, USA. 7Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. FIRC Institute of Molecular Oncology, 20139 Milan, Italy. Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, B-9052 Ghent, Belgium. Basic Medical Sciences, and Purdue University, West Lafayette, Indiana 47907.


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