Boosting Cancer Therapy

Protein snippets prompt tumors to soak up more than 300 percent of the normal amount of chemotherapy drugs.

by Lori Oliwenstein

A panel of breast cancer experts led by top breast cancer surgeon Melvin J. Silverstein, M.D., director of the Harold E. and Henrietta C. esearchers from the USC/Norris Comprehensive Cancer Center have isolated a protein fragment derived from the cancer immunotherapy drug interleukin 2 (IL-2) that seems to enhance the uptake of chemotherapeutic agents into tumors.

In fact, says Alan Epstein, M.D., Ph.D., professor of pathology at the Keck School of Medicine of USC, when this protein fragment is attached to a tumor-targeting antibody, it can prompt tumors to soak up more than 300 percent of the normal amount of chemotherapy drugs.

It does this, Epstein says, by making the tumor’s blood vessel walls more “open” or permeable to the drugs. Blood vessel walls are made of epithelial cells that are usually tightly joined together; when the junctions between those cells loosen up, it becomes easier for molecules to enter or leave the bloodstream.

The interleukins are part of a class of proteins called cytokines, which play a role in the human immune response. It has been hoped that IL-2 and its brethren might play a central role in cancer immunotherapy—battling cancer by revving up the immune system. Unfortunately, IL-2 can only be tolerated in small doses by the body. Taken at levels that would take advantage of its therapeutic value causes widespread edema and other problems due to blood vessel leakiness.

While seeking the cause of this leakiness, Epstein and his colleagues isolated a stretch of amino acids on the IL-2 protein; this sequence, he says, “is responsible for 100 percent of the permeability of the blood vessel walls.” Dubbed PEP, for permeability-enhancing peptide, the patented molecule is being commercially developed by Peregrine Pharmaceuticals Inc. of Tustin, Calif.

Having determined that PEP makes vessels more permeable, Epstein and his colleagues took their exploration a step further, into mouse studies.

The researchers gave chemotherapy to mice with cancerous tumors. Those who had received a PEP treatment beforehand absorbed three to four times as much of the chemotherapy drug as mice not treated with the PEP preparation.

“We’ve shown that you can use PEP to induce selective and reversible blood vessel permeability at the tumor site to get better drug uptake,” says Epstein. “This may turn out to be a hugely important tool in cancer therapy.”

The next step, he says, “is to try to get this product ready to test in human patients.”

This work was described in the May 21 issue of the Journal of the National Cancer Institute and was supported by grants from the National Cancer Institute, Peregrine Pharmaceuticals Inc. and Cancer Therapeutics Laboratories.