September 9, 1999 Contact: UIC: Bill Burton (312) 996-2269, burton@uic.edu

TURNING OFF CANCER SHIELD MAY ALLOW SAFER CANCER THERAPY

In a strange twist that may point the way to more effective cancer treatment, a team of researchers has shown that deactivating one of the body's key cancer-protection shields may offer a surprisingly simple way for doctors to lessen the debilitating and life-threatening side effects of chemotherapy or radiation.

In the Sept. 10 issue of the journal Science, a research team from the University of Illinois at Chicago, working with Quark Biotech, Inc. (QBI), a Pleasanton, Calif.-based biotechnology company, reports finding a new drug called pifithrin-alpha that in mice protects vulnerable healthy tissues from the dangerous side effects of radiation therapy.

Pifithrin works by temporarily blocking the action of a molecule called p53, the granddaddy of a group of intensively studied compounds known as tumor-suppressors, which healthy cells in the body produce to protect themselves from turning cancerous. Approximately 60 percent of all human cancers do not have a functioning p53, which normally acts as a brake on cell division and tells a damaged cell to commit suicide for the greater good of the whole organism - a process called apoptosis.

For the past 20 years, scientists have focused on ways of restoring p53 function to cancerous cells that had lost it, hoping to encourage those cells to destroy themselves. Turning that logic around, a team led by Andrei Gudkov, associate professor of molecular genetics at UIC, reasoned that a drug that could block p53 might prevent the massive die-off of healthy cells in the blood-forming system and intestinal tract and thus allow chemotherapy or radiation to be administered more safely. These healthy cells, unlike most tumors, have a working p53 that causes them to die in large numbers when damaged by such agents.

"Inactivation of p53 has always been considered an unfavorable event," said Gudkov. "But our approach was to temporarily and reversibly suppress p53 during radiation so that healthy cells would not self-destruct in response to damage from life-saving therapy." Because most tumors lack p53 anyway, a drug that suppresses p53 will not help tumor cells escape eradication but will only help healthy cells survive.

Researchers also hope that diminishing the harmful side effects would allow higher doses of therapy to be administered to improve cure rates.

To identify a compound that could block the action of p53, the researchers created a model of normal tissue containing a reporter gene that turns cells blue when p53 is activated. They treated the cultured mouse cells with 10,000 man-made compounds to see if any would suppress p53 when the cells were subjected to the chemotherapy agent doxorubicin.

From among a few test compounds that suppressed p53, the team selected one that in the absence of doxorubicin did not affect cell growth or survival, even at high concentration. This compound, which is water-soluble and stable, they named pifithrin for "p53 inhibitor."

The researchers found that an injection of pifithrin could protect mice from a radiation dose that would normally kill 60 percent of the animals, and some mice survived even higher doses of radiation when given pifithrin. Mice treated with pifithrin also lost much less weight due to radiation than did the few irradiated survivors that did not receive the drug.

Because it turns off healthy cells' primary shield against cancer-causing radiation damage, the treatment strategy carries a theoretical risk. But the researchers showed that the effects of pifithrin were temporary and reversible, and none of the 30 test animals that survived radiation and pifithrin treatment had developed tumors or other lesions even seven months later.

"The results of our study may translate into a new concept for using p53 in cancer treatment that would help cancer patients who suffer from incapacitating side effects," Gudkov said.

"This is a novel concept - to be able to suppress the damage of chemotherapy and X-rays with a drug, and it looks like it works extremely well," said David Patterson, president of the Eleanor Roosevelt Institute for Cancer Research, who was not involved in the study.

The UIC and QBI investigators estimate the compound may be in Phase-I clinical trials within a year. UIC and QBI will continue development jointly. The company is licensed to commercialize new applications of its joint discoveries with UIC, while the university holds the patents.

First authors on the Science report are husband and wife researchers Pavel Komarov and Elena Komarova of UIC; Roman Kondratov, a visiting scholar at UIC; Konstantin Christov-Tselkov, a research assistant professor in surgical oncology at UIC; John Coon, a pathology professor at Rush-Presbyterian St. Luke's Medical Center; and Mikhail Chernov of the Cleveland Clinic.

Funding was provided by the National Cancer Institute and QBI.

With 25,000 students, the University of Illinois at Chicago is the largest and most diverse university in the Chicago area. UIC is home to the largest medical school in the United States and is one of the 88 leading research universities in the country. Located just west of Chicago's Loop, UIC is a vital part of the educational, technological and cultural fabric of the area.

Quark Biotech, Inc. (QBI) is a privately held biotechnology company engaged in pathology-specific gene discovery designed to identify, select and validate genes and gene products as diagnostics and drug candidates in virtually every disease category. QBI's integrated platform of complementary functional genomic and bioinformatic technologies focuses on the critical genes responsible for the pathways essential to pathogenesis and distinguishes those valuable few, which are well-suited for drug development. QBI has collaborations with several pharmaceutical partners including The Perkin-Elmer Corporation, Sankyo Co., Ltd., Fujisawa Pharmaceutical Co. Ltd. and the Mitsubishi Chemical Corporation. Based in Pleasanton, Calif., QBI has research facilities in Israel, and also conducts research in laboratories in Chicago and the San Francisco Bay area.

-UIC-