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David Bradley ISSUE #56
June 2006
A Basic Approach to Chemotherapy
Jeffrey Krise
Jeffrey Krise

The elusive magic bullet of cancer chemotherapy may be nothing more than a false hope, but now chemists at the University of Kansas have found a way to attack malignant cells with an anticancer drug, while sparing healthy cells. The discovery could allow higher, more effective doses to be administered to cancer patients without increasing the potentially debilitating side effects.

Normal cells simply isolate basic (as opposed to acidic) chemicals, allowing them to be excreted by the cell before they have a toxic effect. In contrast, cancer cells do not function normally and cannot isolate such substances for secretion so they feel the full caustic effects of such compounds. Unfortunately, most anticancer drugs do not fall into this category and accumulate in both normal and malignant cells, causing harm to both. The elusive magic bullet drug and countless attempts to target only cancer cells have had many successes, however, they generally fall short of the target leading to severe side-effects in many patients nevertheless.

Now, Jeffrey Krise of the University of Kansas at Lawrence and colleagues Muralikrishna Duvvuri, Samidha Konkar, Kwon Ho Hong, and Brian Blagg reasoned that if there were a way to make anticancer drugs basic then they could essentially target only cancer cells, as healthy cells quickly isolate and excrete basic compounds. They have tested this approach successfully on several existing anticancer drugs—inhibitors of the Hsp90 molecular chaperone—in the laboratory and say it could offer substantial benefits for cancer patients.

"It could allow cancer patients to tolerate higher and more effective doses of chemotherapy before normal cells are damaged to an extent that causes serious side effects and cessation of therapy," Krise explains. "The approach is completely different from previous attempts that were designed to deliver drugs only to cancer cells and not normal cells." He suggests that his team's findings offer a new rational approach to designing selective anticancer drugs that have fewer side-effects. "Importantly," he adds, "this technology can also be used to modify existing drugs and increase their selectivity."

Krise's report describes a number of existing anti-cancer drugs that have basic properties, and notes that the new findings may provide the first explanation of why these drugs are so effective.

Geldanamycin parent structure of some basic anticancer drugs (Structure created in ChemSketch by David Bradley)

ACS Chem Biol, 2006, in press http://dx.doi.org/10.1021/cb6001202