Chemical warfare on cancer

Oct 7, 2004

Working at the most basic molecular level, Kettering researchers use chemistry to explore new ways to fight cancer.

It sounds like the stuff of science fiction thrillers - "Ali Zand and his team investigate the inhibition of Matrix Metalloproteinases to starve the enemy by cutting off new food supply routes." In reality, their research involves chemically inhibiting pathways that alter normal human tissues and promote the growth of cancer cells.

Ali Zand is still the protagonist, but the Kettering associate professor of Chemistry doesn't wear high-tech science fiction battle gear as often as he wears a lab coat. Zand is part of a team of scientists and physicians collaborating on new techniques for treating cancer.

One of their research projects is the design and synthesis of inhibitors of collagenases, enzymes that play key roles in angiogenesis or the formation of new blood vessels. "These compounds (drugs) are not treating the tumor itself," said Zand, "but are treating the tissues surrounding the tumor where new blood vessels need to form to feed the growing tumor (antiangiogenic). By inhibiting the formation of new blood vessels, they essentially starve tumors to death," he said.

"Cancer is a very invasive tissue, it likes to invade surrounding tissue and it divides very efficiently and rapidly," Zand said, "so it needs a large blood supply. Normally, cancer softens the healthy tissue around the tumor so new blood vessels will start to grow, providing it with much-needed nutrients."

Generally, unless an individual has an injury or some kind of disease that requires a constant supply of blood to a specific area; the body does not generate new blood vessels.

Cancer requires that the body creates new blood vessels in order to feed its voracious appetite. In order for the new blood vessels to form, the surrounding dense connective tissue (which consists mostly of collagen) must be softened so that these newly formed vessels can move through it. "Cancer has to first break down this dense tissue that is hard, and soften it up before the blood vessels can start forming." said Zand.

He is collaborating on the project with Dr. Stacy Seeley, associate professor of Chemistry at Kettering University, and Dr. Andrew Saxe, M.D., director of Surgical Education, at McLaren Regional Medical Center, and professor, Department of Surgery , Michigan State University. Funding for the research project was provided by the McLaren Foundation.

"Our idea is that if we can inhibit these enzymes (collagenases) that assist in breaking down of the connective tissue, then the tissue will never go soft and the body won't be able to form new blood vessels that would supply cancer cells with nutrients. Therefore we could manage the size of the cancer and even at some point starve it to death," he said.

Inhibiting the collagenases does not change the blood vessels that currently exist, they remain intact. Only the formation of new blood vessels is inhibited. This means an invasive tissue like cancer has to limit itself to the supply of blood (nutrients) that is already available and its growth will be slowed or stopped.

Inhibition of these enzymes may stop the tumor from metastasizing as well. "For example," said Zand, "for liver cancer to get into the lymph tissue or blood and go to the lungs or somewhere else, it has to go through this dense connective tissue (collagen). It cannot migrate through the dense tissue very easily unless it has been softened up by the collagenases. Also, by inhibiting the formation of new blood vessels we can stop the metastasis of tumor by providing a convenient mode of travel, the blood, and thus help maintain the invasiveness of the cancer."

"The reason cancer is such a horrendous disease is because if it remains untreated it is going to go all over the place," Zand said. "If it is competing with healthy cells, it is a lot more aggressive and the healthy cells are not going to get what they need. The healthy cells will shrink and die and the cancer cells will take over. If we can manage cancer cell growth, we can stop the tumor in its tracks," he said.

"The enzyme that we have worked on is a bacterial collagenase. We're planning on working with human collagenases" said Zand. The bacterial collagenase was chosen for the initial studies because it is cheaper than human enzyme, but it is very similar as far as the binding to the human collagenases. "In addition, we had the proper equipment to work with the bacterial collagenase at Kettering"

"Essential equipment needed to work with the human enzymes is not available at Kettering," said Zand, "We have to go to Oakland University or Michigan State University to work with the human enzymes."

Research at the molecular level is the first phase in any pharmaceutical research, "essentially test-tube chemistry," according to Zand. The next phase after enzyme research is animal research, with the final phase being tests on human models. "There are a lot of drugs that show impressive activity in test-tube chemistry, but when you actually put them in a human or animal model they don't do well. This may be because by the time they get to the targeted place, body fluids may have changed the structures of these drugs so much that they might not have any activity," said Zand. "Researchers have to show very good results in the first two phases before they can get FDA approval for human testing."

"There are different stages at which you can inhibit the formation of blood vessels' he said, "We are working on one of the earliest phases in inhibiting blood vessel development. There are only one or two antiangiogenic drugs that I know of that have been approved for treatment of cancer," he said.

As Zand and his co-researchers continue their research with human collagenase, they may actually achieve super hero status for their contributions toward cancer fighting treatments. Maybe he should look into finding a set of high-tech science fiction battle gear - or at least superman pajamas.

Written by Dawn Hibbard
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