Stopping leaks may boost cancer drugs

Science News, April 10, 1999 by J. Travis

Almost every medicine produces side effects. The crucial issue is whether a drug has a therapeutic window, a dose range that allays a patient's illness without causing greater problems.

In a finding that may widen the therapeutic windows of two experimental cancer medicines, researchers have uncovered the molecular explanation for a side effect--leaky blood vessels--that both therapies cause. Known as vascular leak syndrome, the condition occurs when fluid from the bloodstream escapes into surrounding tissues.

"You sort of become a water balloon," says Ellen S. Vitetta of the University of Texas Southwestern Medical Center at Dallas. While a body can often slowly expel this excess water, fluid buildup in organs such as lungs can turn deadly.

Vitetta and her colleagues encountered vascular leak syndrome when they began testing immunotoxins in cancer patients. These artificial proteins consist of a plant or bacterial toxin attached to antibodies that home in on cancer cells.

The immunotoxins have lived up to their billing as cancer killers, but they also trigger changes in cells lining blood vessels. The cells become rounder than normal, leaving gaps through which fluid could seep out. The problem limits the amount of immunotoxins people can receive as a treatment.

"This has stalled the field a great deal," says immunotoxin investigator Daniel A. Vallera of the University of Minnesota Cancer Center in Minneapolis.

"You don't have a wide therapeutic window, because you hit this toxicity," agrees Christopher A. Pennell, also of the University of Minnesota Cancer Center.

Like the immunotoxins, interleukin-2, a protein that stimulates the immune system's cells, causes vascular leaks at high doses. The side effect has frequently thwarted its use in people with cancer and, more recently, AIDS.

Speculating that immunotoxins and interleukin-2 generate leaky blood vessels in the same way, Vitetta's team compared the proteins. "You line up the [amino acid] sequences and ask if there's a consensus sequence. Lo and behold, out came this motif," says Vitetta. All the molecules share a particular combination of three amino acids, her group reports in the March 30 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

The researchers also made protein fragments containing this motif but no other parts of interleukin-2 or the immunotoxins. Injected into animals, those segments caused leaky blood vessels. "You don't need the rest of the molecules," says Vitetta. "You just need this tiny, little piece."

The scientists are now trying to eliminate this dangerous motif by mutating the genes that encode the immunotoxins. They expect that the modified immunotoxins will retain their cancer-killing prowess but leave blood vessels alone.

Making interleukin-2 safer may prove more difficult since the motif falls in a region crucial to the protein's therapeutic function. Investigators could instead try to block the proteins on blood vessels that the immunotoxins and interleukin-2 bind, Vitetta notes.

"She's putting together a really nice story," says Pennell.