BioWorld International Correspondent

LONDON - A peptide that can induce several different types of cancer cells to enter apoptosis (programmed cell death) could lead to the development of new anticancer agents.

The protein fragment, called 37AA, works by activating a protein called p73. 37AA is made up of two evolutionarily conserved regions from the protein p53, fused together.

In a mouse model of cancer, infusing particles containing 37AA into the blood stream caused tumors to regress.

p73 is a member of the p53 group of proteins, which are well known for their ability to switch a cell that has DNA damage into cell cycle arrest or even trigger cell death. p53 is mutated in about 50 percent of human cancers.

"Our study has shown for the first time that the selective activation of a gene called p73 can cause cell death in tumors," said Kevin Ryan, senior research fellow at Cancer Research UK and head of the Tumour Cell Death Laboratory at the Beatson Institute for Cancer Research in Glasgow, Scotland. "We think this approach has the potential to be developed into an effective treatment for cancer."

The next phase of the research will focus on developing a drug that mimics the effect of 37AA. "We hope that it will then be possible to test this strategy more readily for its potential development in human tumors," Ryan added.

Ryan and his colleagues report their work in a paper in the March 8, 2007, Journal of Clinical Investigation titled: "A novel p53-derived apoptotic peptide de-represses p73 to cause tumor regression in vivo."

The study was funded by Cancer Research UK with support from the Biotechnology and Biological Sciences Research Council and the Ludwig Institute for Cancer Research.

For the animal studies reported in the journal, Ryan and his collaborators used nanoparticles made from lipid components called polypropylenimine dendrimers. They engineered those to contain DNA complexes that included transgenes encoding 37AA.

Commenting on the paper, Jim Cassidy, Cancer Research UK's chair of medical oncology in Scotland, said, "This fascinating piece of basic research has resulted in an experimental treatment that can cause malignant tumors to stop growing. In laboratory tests, it killed a range of different cancer cells. We look forward to seeing if switching on p73 can translate into a treatment for patients."

In the past couple of decades, much research into the causes and possible treatment of cancer has focused on trying to activate the protein p53, because of its anti-cancer properties.

Normally, in any cell that develops abnormalities such as DNA damage or activation of oncogenes, p53 induces cell-cycle arrest - allowing cellular damage to be repaired - or triggers apoptosis.

Researchers have therefore hoped that activating p53 could help to eliminate cancer cells from the body. But because p53 is mutated in such a high proportion of human cancers, activating that protein is not always an option.

Ryan and his colleagues decided to investigate genes and proteins that lie downstream of p53. They focused on p73 because it seemed to have similar functions to p53, but was rarely mutated in human cancers.

The researchers' paper reported their work on how to activate p73.

They discovered that 37AA - a peptide of 37 amino acids - can bind a protein called iASPP. The latter acts on the p53 family of proteins, acting as a brake on their ability to send the cell into the apoptotic pathway. When they added 37AA to cells that lacked p53, they found that it activated p73, lifting the brake, and triggering the cells to enter apoptosis.

Further experiments showed that when they infused the nanoparticles containing 37AA into mice that had experimental tumors, the tumors regressed. Other studies showed that 37AA could kill several types of cancer cells, including bowel, cervical and bone cells.

Ryan told BioWorld International: "The next phase of our work will involve trying to find a small molecule that mimics the effects of 37AA, and which has the right characteristics in terms of solubility and delivery method to be used as a drug. But we can't predict how long this search will take."

Ryan and his colleagues concluded in the journal: "This study . . . heralds the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease."