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Nongenotoxic p53 Activation Protects Cells against S-Phase–Specific Chemotherapy

¹ Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, Odense, Denmark and ² Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, University of Göttingen, Göttingen, Germany

Requests for reprints: Matthias Dobbelstein, Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, University of Göttingen, Justus von Liebig Weg 11, D-37077 Göttingen, Germany. Phone: 49-551-39-13840; Fax: 49-551-39-13713; E-mail: mdobbel{at}uni-goettingen.de.

Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy. (Cancer Res 2006; 66(21): 10274-80)

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