Peptides could be efficacious for colon cancer treatment, detection

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Gastroenterology researchers at the Johns Hopkins School of Medicine were surprised to find, while tagging peptides to see how well they bonded to colorectal cancer cells, that the radioactive phosphorous 32P tag was actually being absorbed into the cancerous cells.

The discovery suggests that such 32P-labeled peptides have the potential for use both as highly effective radiation treatment delivery systems and as a method of detecting cancerous cells and growths in the colon, according to John M. Abraham, PhD, and Stephen J. Meltzer, MD, both of the department of gastroenterology and hepatology at the university.

Abraham and Meltzer both said they did not set out to test radiation cell-delivery systems, according to RSNA News.

“The original design of the experiments employed 32P merely as a tag that could easily be followed and quantified,” said Abraham, an assistant professor of medicine. He added that 32P is primarily used to treat red-blood cell polycythemia and platelet essential
thrombocythemia. “It was a surprise when we discovered that the 32P was actually being incorporated into the cellular proteins. After that, we began to research whether this radioisotope might be used therapeutically.”

Abraham said the discovery raises the possibility that 32P or similarly tagged peptides could deliver radiation treatment directly into the “heart” of a cancerous cell, rather than bombarding it from the outside, which could be especially effective on thick colon cancer tumors, which are often more resistant to drug penetration.

“In the world of molecule therapeutics for the treatment of tumors, the belief is that smaller is better—the smaller an agent is, the better it can penetrate the tumor,” said Abraham. “An antibody molecule is gigantic compared to the tiny peptides we are using—our tiny peptides are less than 3 percent of the size of an antibody molecule.”

The therapy might also mean patients would experience fewer side effects such as nausea, gastrointestinal bleeding and low blood cell counts.

“Peptides penetrate into tumors more easily and are more rapidly excreted by the kidneys, in turn reducing systemic toxicity,” said Meltzer, the Harry and Betty Myerberg/Thomas R. Hendrix professor of gastroenterology and director of the Early Detection Biomarkers Laboratory at Johns Hopkins. Because the peptide contains the human enzyme protein A substrate, the body’s immune system may not attack it, Meltzer added.

“The initial experiments used peptides of many different sizes, and one of the first peptides that resulted in extremely strong results happened to be a decapeptide with 10 amino acids,” Abraham added.

While generating additional small 32P-labeled peptides, the researchers found that “of the nine members of the decapeptide family described in our recent paper, peptide MA5 bound best and transferred more radioisotope to cell lines derived from the human colon adenocarcinomas,” according to the researchers.

“The peptides vary from one another by one to three amino acids, and these slight changes can make a great difference in their cellular binding and transfer abilities. We think that this random generation strategy will give us an unlimited library of peptides to choose from in designing and matching individualized therapies,” Meltzer said.