Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Antineoplastic Agents/*therapeutic use ; Peptides/*therapeutic use ; Peritoneal Neoplasms/*therapy ; Tumor Suppressor Protein p53/*metabolism; Cell Division/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, p53/drug effects ; Genetic Therapy ; Humans ; Peritoneal Neoplasms/pathology ; Protein Processing, Post-Translational ; Transcriptional Activation ; Tumor Suppressor Protein p53/genetics

Advanced-stage peritoneal carcinomatosis is resistant to current chemotherapy treatment and, in the case of metastatic ovarian cancer, results in a devastating 15%-20% survival rate. Therapeutics that restore genes inactivated during oncogenesis are predicted to be more potent and specific than current therapies. Experiments with viral vectors have demonstrated the theoretical utility of expressing the p53 tumor suppressor gene in cancer cells. However, clinically useful alternative approaches for introducing p53 activity into cancer cells are clearly needed. It has been hypothesized that direct reactivation of endogenous p53 protein in cancer cells will be therapeutically beneficial, but few tests of this hypothesis have been carried out in vivo. We report that a transducible D-isomer RI-TATp53C' peptide activates the p53 protein in cancer cells, but not normal cells. RI-TATp53C' peptide treatment of preclinical terminal peritoneal carcinomatosis and peritoneal lymphoma models results in significant increases in lifespan (greater than 6-fold) and the generation of disease-free animals. These proof-of-concept observations show that specific activation of endogenous p53 activity by a macromolecular agent is therapeutically effective in preclinical models of terminal human malignancy. Our results suggest that TAT-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to malignant cells in vivo.
Competing Interests: SFD is the scientific founder of Ansata Therapeutics, a biotech company utilizing protein transduction technology to treat human disease. However, he owns less than 5% of the stock, does not receive any research funds from Ansata, does not have a seat on the board of directors, and has no say in the governance of the company.

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R01 CA096098 United States CA NCI NIH HHS; CA96098 United States CA NCI NIH HHS

0 (Antineoplastic Agents)
0 (Peptides)
0 (Tumor Suppressor Protein p53)
0 (retro-inverso-TATp53C' peptide)

Date Created: 20040218 Date Completed: 20060303 Latest Revision: 20220317

20221213

PMC340944

10.1371/journal.pbio.0020036

14966535