By David N. Leff

In this millennium-ending time of violence, a dangerous occupation is that of "innocent bystander." Likewise, at the military level, "friendly fire" kills innocent by-standing soldiers.

At the cellular level, "side effects" of well-calculated anti-cancer therapies knock out healthy cells standing too close for comfort to the drug-targeted tumors. In a sense, the untoward adverse events spun off by high-dose chemotherapy and radiation treatment make the cure worse than the cause. For example, many patients can't tolerate the unremitting, debilitating nausea and vomiting brought on by cytotoxic drugs, so dosing has to be reduced below levels that might be most effective against the cancer.

Another price that patients must pay is temporary but agonizing hair loss. What's more - much more - tissue-destroying anti-cancer compounds wreak life-threatening side-effect havoc with the body's internal organs.

"Hair loss is bad cosmetically, but it's not dangerous," observed molecular geneticist Andrei Gudkov at the University of Illinois, in Chicago. "If we speak about the general effects of any type of genotoxic stress - it could be gamma irradiation or chemotherapy - all these drugs and treatments are targeting and damaging DNA. And all of them are going through p53.

"There are three major places where dangerous side-effect damage is occurring," Gudkov said. "First of all in the blood-forming, hematopoietic system and the immune system - which is the natural defense mechanism against cancer.

"Another critical site," he noted, "is the digestive tract, which extends from mouth to rectum. One part of the digestive tract that's particularly sensitive is the small intestine, which has high levels of p53 protein in its stem cells. So it's more sensitive to apoptosis - programmed cell death. And the third heavily damaged place is the reproductive system. Many patients who pass through cancer treatment become sterile."

Apoptosis is the key molecular assault weapon that perpetrates all this cellular mayhem. And the finger that pulls its trigger, paradoxically, is p53 - the tumor-suppressor of choice. Normally, p53 patrols the body to ward off malignant transformation. It acts as a brake on runaway cell division, and orders damaged cells to commit suicide for the greater good of the body as a whole. But where tumor suppression fails, six out of 10 human cancers are found to harbor a defective, mutated, p53 protein.

Saving Healthy Cells From Themselves

For the past 20 years, oncologists have been seeking ways to restore p53 tumor-suppressing function to cancerous cells that had lost it. They aimed at pushing those cells to kill themselves. Gudkov took aim instead at the normal bystander cells that p53 destroys. He reasoned that a drug able to block p53 might prevent the wholesale die-off of healthy cells.

Such a compound, Gudkov predicated, would let chemotherapy and radiation proceed more safely and effectively. He is senior author of a research report in today's Science, dated Sept. 10, 1999, titled: "A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy."

To find such an inhibitor, he and his co-authors screened a library of 10,000 diverse chemicals against two mouse cell lines - one that carried the wild-type p53 gene, the other capable of p53-dependent apoptosis. To these, they added cytotoxic doxorubicin (adriamycin), a potent p53-inducer, and cancer chemotherapeutic.

The team came up with a synthetic, water-soluble compound, molecular weight 367, that blocked p53 activation. "We named it," Gudkov told BioWorld Today, "pifithrin-a (PFT-a), an abbreviation for 'p-fifty three inhibitor.'"

After extensive in vitro assays, the co-authors tested their PFT-a in two different strains of mice. They exposed these animal models to the effects of their inhibitor compound on sublethal and lethal whole-body gamma radiation. "PFT-a treatment," Science reported, "completely rescued mice of both strains from 60 percent-killing doses of gamma irradiation." Significant protection was also seen at higher doses of irradiation that were lethal for control animals.

The co-authors added that "in our study, no tumors or other pathological lesions were found in the group of 30 survivors rescued from lethal gamma irradiation by PFT-a, even at seven months after irradiation."

These results, they concluded, "raise the possibility of using PFT-a (or other compounds with similar activity) to reduce the side effects of radiation therapy or chemotherapy for human cancers that have lost functional p53." (Gudkov noted that "Gamma irradiation nicely imitates the side effects of all chemotherapeutic drugs, but every one of these has its own side effects on top of that.")

Primates Await Next-Generation p53-Inhibitor

Gudkov foresees Phase I clinical trials "within a year - but not yet, because important parts are still missing." First of all, he said, "we now have a better candidate than PFT-a. PFT-b is a derivative that, although as efficient as a, is much less toxic. So obviously we need to do at least a limited large-animal trial to ensure it's not toxic for primates. After that we will go into Phase I trials.

"Our program," Gudkov noted, "is funded through a research grant from Quark Biotech, of Pleasanton, Calif. They are taking an exclusive license from the university on our concept, for which a patent is pending. And Quark will be funding the clinical trials and future development.

"There are some other potential applications of our approach," he said, "because it need not be limited to cancer. Let's consider heart and brain ischemia. These are the main targets for our present testing of PFT-b, because apoptotic death occurring in neurons during stroke might involve p53 as a component. We have to do many more experiments to see if that's going to work."

Gudkov noted that "Inactivation of p53 has always been considered an unfavorable event, but our approach is to suppress p53 temporarily and reversibly during radiation or chemotherapy, so that healthy cells won't self-destruct in response to damage from life-saving anti-cancer treatment. Because most tumors lack p53 anyway, a drug that suppresses it will not help cancerous cells escape eradication, but only help healthy cells survive."