How A Common Protein Becomes A Cancer Killer

August 31, 1998

MADISON--In one of nature's remarkable flukes, scientists in 1991 discovered a protein in frog eggs that proved to be a potent killer of cancer cells. Now a new study by a University of Wisconsin-Madison biochemist finds that a "cousin" of that frog protein found in mammals has the same cancer-fighting potential.

Biochemist Ron Raines reports in the Sept. 1 Proceedings of the National Academy of Sciences that ribonuclease A - a digestive protein made by the pancreas - could be genetically altered to kill cancer cells. The finding opens a door to creating a new class of "natural" drugs aimed at fighting cancer, without the side effects of standard chemotherapy, he said.

"The greatest advantage could be as a potential new pathway for cancer therapy," Raines said. "With this finding, we can also begin to think about tailoring proteins to work more effectively against specific forms of cancer."

Raines' research questions begin with the 1991 discovery that a ribonuclease protein in the Northern leopard frog possesses anti-cancer properties. The New Jersey-based biotechnology firm Alfacell Corporation, which is credited with the discovery, is manufacturing a drug called Onconase that is currently in phase-three clinical cancer trials.

Delivered to patients intravenously, Onconase has shown promising results in treating malignant mesothelioma, an asbestos-related cancer. In recent years, a National Institutes of Health (NIH) study also found that Onconase inhibits the replication of the HIV virus.

Raines set out to answer an essential question about Onconase: What makes this frog-derived protein such an effective cancer toxin, compared to its genetically similar "cousin" in humans? Raines found the answer by comparing the molecular structure of the protein produced by frogs with a similar ribonuclease protein in cows. Bovine ribonuclease is very similar to the human form.

Raines found the two proteins differ in their ability to bind with a ribonuclease inhibitor (RI). This inhibitor is found in nearly every cell in the body, and keeps ribonuclease from attacking and breaking down cellular RNA.

"The RI protein acts as a sentry inside the cell, protecting the cell's RNA against invasion by ribonuclease," Raines said. "But Onconase does not bind effectively with this inhibitor, which makes it free to seek out and kill other cells."

Raines said it is not entirely clear why the ribonuclease attacks only cancer cells, yet is otherwise gentle to healthy human cells. One possibility is there are unique receptors on the outside of cancer cells that bind more tightly to ribonucleases.

The researchers were then able to create, with a bovine form of ribonuclease, two variant strains of the protein that did not bind tightly to the inhibitor. Those variants that evade RI were proven in laboratory tests to be lethal to cancer cells.

"We've been able to show in this study that there is no special property of Onconase that makes it distinctly different from related ribonucleases," Raines said. "In fact, human ribonuclease has everything needed from a molecular standpoint to be cytotoxic to cancer."

This is a valuable insight for producing a new class of cancer-fighting medications that, unlike other chemotherapies, act as "biocompatible toxins" that kill cancer cells without causing secondary damage in patients, Raines said.

His lab is currently working on creating variant strains of human ribonuclease that can produce the same cancer-fighting effects. Using a human protein is less problematic than integrating a substance that is foreign to the human body, he said.

Raines' lab is funded by the National Cancer Institute, an affiliate of NIH, to investigate the novel properties on Onconase.

University of Wisconsin-Madison

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