Peptide Activator Of p53 May Treat Peritoneal Carcinomatosis

NEW YORK (Reuters Health) - A transducible p53-activating peptide increases survival in animal models of peritoneal carcinomatosis and peritoneal lymphoma, according to a report in the February issue of Public Library of Science Biology.

Current chemotherapeutic approaches often prove ineffective against advanced-stage peritoneal carcinomatosis and disseminated peritoneal lymphoma, the authors explain. Strategies designed to restore p53 activity might induce cancer cell death and thereby benefit a large fraction of cancer patients.

Dr. Steven F. Dowdy from University of California, San Diego, La Jolla, California and colleagues tested whether a stable p53C' peptide -- previously shown to activate DNA binding by p53 -- is a therapeutically effective means of activating the p53 tumor suppressor pathway in preclinical models of terminal metastatic cancer.

The genetically engineered p53C' peptide (RI-TATp53C') appeared specifically to activate p53 in mammary carcinoma, human lung carcinoma, and colon carcinoma cell lines, the authors report.

Intraperitoneal injection of RI-TATp53C' significantly retarded the growth and reduced the final mean volume of distant solid tumors in immune competent mice, the report indicates.

Moreover, the researchers note, treatment with RI-TATp53C' in a terminal peritoneal carcinomatosis mouse model increased the mean survival time from 11 days to more than 70 days after tumor inoculation.

RI-TATp53C' treatment was similarly effective in a mouse model of aggressive, disseminated peritoneal lymphoma, the results indicate, extending mean survival time from 33 days to more than 200 days after tumor cell injection.

Treatment failures were not due to the acquisition of resistance to the RI-TATp53C' peptide, the investigators report. They suggest "that an extended treatment protocol may lead to a further enhancement of survival in these preclinical cancer models."

"This paper shows that delivery of biologics in preclinical models has therapeutic efficacy," Dr. Dowdy told Reuters Health. "However, the key thing to remember here is that this paper serves as a proof-of-principle. There is still a lot of preclinical work that needs to be done."

"We are also currently testing several other anti-tumor cargos with enhanced activity than the p53 C-terminal peptide used here," Dr. Dowdy said. "Our goal is a multi-domain peptide/protein where we add additional domains that both increase specificity for tumor cells and further enhance the delivery into cells."

He added, "We need to evaluate many tumor types in this preclinical peritoneal model before we can decide what we would focus on in eventual clinical trials. However, due to the devastating consequences and inability to successfully treat a high percentage of patients, metastatic ovarian peritoneal carcinomatosis and lymphoma are high on our list."

Source: PloS Biology 2004;2:e36.doi:10.1371/journal/pbio.0020036 [ Google search on this article ]

MeSH Headings: DNA-Binding Proteins : Nuclear Proteins : Phosphoproteins : Transcription Factors : Viral Proteins : Viral Regulatory Proteins : Trans-Activators : Protein p53