Compelling cancer cells to self-destruct.

Compelling cancer cells to self-destruct

A cell's surface begins to blister, its nucleus disintegrates and the surrounding cytophasm shrinks. Finally, with its DNA breaking into short "ladders," the cell dies. This phenomenon, called programmed cell death, occurs naturally in developing embryos, skin and metamorphosing insects--wherever certain cells are no longer needed (SN: 12/5/87, p.360).

Now west German researchers have triggered programmed cell death in human tumor cells. Using a monoclonal antibody with no attached drug or toxin, the scientists killed malignant regression of vitro and caused striking regression of human tumors growing in immunologically weakened "nude" mice.

The newly engineered antibody, called anti-APO-1, may eventually offer a novel approach for treating some cancers, says study coauthor Peter H. Krammer. But its therapeutic potential, he cautions, "very much depends on how much any normal tissue is affected [by the antibody]." He and his colleagues at the German Cancer Research Center and the University of Heidelberg are now testing anti-APO-1 for ill effects on noncancerous tissue.

To produce the deadly antibody, Krammer's group injected normal mice with cancerous human B-cells, a type of white blood cell. They then extracted and cultured antibody-secreting cells from the mice and tested antibodies from more than 10,000 cell cultures. Antibodies from one culture completely blocked growth of the cancerous cells, they report in the July 21 SCIENCE.

Under the microscope, the cancerous cells revealed blisters and other changes suggesting programmed cell death. In contrast, cells killed by antibody-actuated immune proteins swell and burst. The scientists also measured the cells' broken DNA, finding the 180-base-pair ladders characteristic of programmed cell death.

The mechanism of this destruction remains unknown. Krammer notes that the immune system's killer T-cells and some cytotoxins such as tumor necrosis factor (SN: 8/31/85, p.132) can also induce programmed cell death.

When anti-APO-1 attaches to a cell surface, "the cell goes berserk," says Krammer. It appears unlikely that the antibody's attachment site -- a protein dubbed APO-1--is the receptor for tumor necrosis factor, he adds. But he speculates that APO-1 may be a receptor for killer T-cells or part of a family of receptors that trigger programmed cell death when stimulated.

The West German group also found APO-1 on some noncancerous immune cells from humans. And that may bode ill for the monoclonal antibody's use in cancer treatment. "It's worrisome that [APO-1] is found on active B- and T-cells," says Ralph Reisfeld of the Research Institute of Scripps Clinic in La Jolla, Calif. If it destroys normal, active immune cells, this could prevent physicians from using the antibody with other treatments, he says. Noting that many newer cancer therapies work by activating killer T-cells to attack tumors, Reisfeld says administering anti-APO-1 in conjunction with these treatments could "throw a monkey wrench into the process."

Still, Reisfeld joins Karl Eric Hellstrom of Oncogen in Seattle in calling the work "exciting." Anti-APO-1 is one of only a few antibodies with direct antitumor effects, says Hellstrom, who describes the tumor reduction in nude mice as "quite remarkable." Hellstrom says he thinks "it would be worthwhile to try to follow up in some clinical model." But he emphasizes the necessity of looking first for toxic effects on normal tissue.