NEW YORK (Reuters Health) - “Nutlins,” a series of synthetic cis-imidazoline analogs, inhibit the oncogene MDM2, thus stabilizing the p53 tumor suppressor protein and inhibiting the growth of malignant tumors, researchers report. Treatment of mice with subcutaneous osteosarcoma tumor xenografts with Nutlin-3 inhibited tumor growth 90% relative to control treatment after 20 days.
The use of MDM2 antagonists “may be applicable not only to tumors with aberrant MDM2 expression but possibly to many of the 50% of all human malignancies that have retained wild-type p53,” write lead investigator Dr. Lyubomir T. Vassilev and colleagues at Hoffman-La Roche Inc., in Nutley, New Jersey report in the journal Science, published online on January 2.
The authors explain that the MDM2 gene is amplified or overexpressed in many human malignancies, which presumably leads to p53 inactivation. Nutlins displace p53 protein from its complex with MDM2, and their findings suggest that MDM2 blockage causes cell cycle arrest or apoptosis or both.
To examine their effect in vitro, they incubated colon cancer cells with wild-type p53 with Nutlin-1, and observed a dose-dependent increase in MDM1, p53 and p21 after 8 hours. Co-culture of Nutlin-1 with cancer cells exhibited an antiproliferative/cytotoxic effect that was more pronounced in cell lines with normal p53 genes or an amplified MDM2 gene.
When normal diploid fibroblasts with a functional p53 pathway were treated with Nutlin-3, the investigators observed reduced proliferation but no change in viability even after 1 week.
The authors note that Nutlin-3 was well tolerated in their in vivo mouse studies, with no weight loss and no apparent abnormalities revealed by necropsy.
“Our data strengthen the notion that unleashing the powerful growth suppressive and pro-apoptotic activity of p53 by MDM2 antagonists is a potentially valuable strategy for treating cancer,” Dr. Vassilev and colleagues write.
Source: Science 2004.www.sciencexpress.org [ Google search on this article ]
MeSH Headings:Cell Line: Cells, Cultured: DNA-Binding Proteins: Nuclear Proteins: Phosphoproteins: Tumor Cells, Cultured: Drugs, Investigational: Genes, p53: Protein p53Copyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
