RESEARCH REVEALS WHY EXPERIMENTAL CANCER DRUG IS INEFFECTIVE

COLUMBUS, Ohio -- New research has revealed why a seemingly promising experimental anti-cancer drug works better in mice than it does in humans.

The drug -- camptothecin -- eradicates human cancers transplanted into mice, but it doesn't work nearly as well in humans with cancer because the drug loses its effectiveness when it enters the bloodstream.

The study found that the effectiveness is lost because camptothecin interacts with albumin, a protein found abundantly in blood. The interaction rapidly converts camptothecin to an inactive form of the drug.

"This is an important effect in blood," said Thomas Burke, assistant professor of pharmacy and a researcher with Ohio State University's Comprehensive Cancer Center. "If we understand it, perhaps we can turn it to our advantage to improve this and other drug treatments.

"Studies have shown that camptothecin can cure human cancers transplanted into mice. Our results indicate that it's not going to be easy to do the same thing in humans."

But that doesn't mean it's impossible.

"Camptothecin still has potential as a therapeutic drug; this study just tells us that we still have much to learn about how it acts in the human system."

The results are also a clear example of the variations that can occur between animal species, he said. "I think they show we have to be cautious about extrapolating information about drug therapy from animal models and applying it to humans."

The albumin found in human blood has a unique capacity to interact with camptothecin, he said. That interaction doesn't occur in mice, which are commonly used in preclinical testing of new drugs.

"The result is that the level of active drug in the blood of mice can be a hundred-fold higher," said Burke. "And that's going to significantly affect the activity of the medication."

The study, done by Burke and graduate student Zihou Mi, was published in a recent issue of Biochemistry.

Modified versions of camptothecin -- camptothecin analogs -- are in clinical trials at a number of centers. The most promising of these, the drug topotecan, is in the final phase of clinical trials. Topotecan doesn't interact with serum albumin in humans as greatly as does camptothecin.

Camptothecin and its analogs are important drugs because they are the only drugs known to block a particular enzyme required for cell division. The enzyme, topoisomerase I, helps DNA unwind so it can replicate. Blocking the enzyme stops cell division, causing cell death and destruction of a tumor.

Burke's study was possible because camptothecin emits visible light -- it fluoresces -- when struck by ultraviolet light.

"By analyzing the drug's fluorescent emission, we can gain detailed information about how camptothecin interacts with other molecules," said Burke. "Most therapeutic agents don't have this property."

How do camptothecin and albumin interact? When camptothecin is taken as a pill, the acid conditions in the stomach keep it in its active form. The acid conditions keep a critical ring structure in the molecule closed.

But then the drug enters the bloodstream. There, the pH is higher -- slightly basic. This causes the ring in some of the drug molecules to open up. In the open-ring form, the drug is much less effective, much less toxic to cancer cells.

In the blood, the open-ring form and the closed-ring form would come to a natural balance, and the effectiveness of the drug might still be sufficient. But albumin proteins in the blood change that balance.

It turns out that the open-ring form of the drug, the inactive form, binds to albumin proteins like iron filings to a magnet. This causes more of the active form of the drug to convert to inactive form, which is again sopped up by serum albumin.

"So in humans there is a cycle that drains the system of the active form of the drug," said Burke.

Albumin proteins in mice, however, have a much weaker affinity for the drug. This leaves a far greater amount of active drug available in the blood to fight a tumor.

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Contact: Thomas Burke, (614) 292-2915

Written by Darrell E. Ward, (614) 292-8456