Starving tumors from inside may pose risks-study

CHICAGO, Aug 24 (Reuters) A study in mice suggests a new way of starving tumors of their blood supply may cause heart attacks and strokes, raising concerns about this type of cancer therapy, US researchers said.

Mice bred to lack a certain gene involved in blood vessel growth suffered strokes and heart attacks, the researchers said yesterday.

Currently, such angiogenesis inhibitor drugs, including Genentech Inc's Avastin, work from the outside of the cell. They have been found to treat several types of cancers with fewer side effects.

Avastin works by blocking vascular endothelial growth factor, or VEGF, a so-called signaling protein that spurs growth of new blood vessels.

But a number of drug companies including Genentech and Novartis AG are looking at small molecule cancer drugs that can get inside cells and block VEGF.

Researchers at the University of California Los Angeles tested this approach in mice that were bred to lack VEGF in endothelial cells, which coat the inside of blood vessels.

More than half of the mice in their study suffered heart attacks and fatal strokes, while those that remained alive became very ill.

''This was an extremely surprising result,'' said Luisa Iruela-Arispe, whose study appears in the journal Cell.

''The concern is that long-term exposure to a drug that targets VEGF from inside the cell could be dangerous and cause heart attacks and strokes,'' Iruela-Arispe said in a telephone interview.

''The study we performed was genetically based,'' she added.

''We didn't use drugs. We tried to remove VEGF that was produced inside the cell.'' She and colleagues did not expect to see a big effect because the amount of VEGF produced inside these cells was minuscule compared to the levels of VEGF created outside the cells.

But 55 per cent of the mice in the study died by 25 weeks of age, which would be the equivalent of age 30 in humans. Mice followed into old age were very ill.

Iruela-Arispe said signaling inside the cell is different from that initiated outside the cell. She said it is not clear whether drugs such as Avastin are dangerous in this way.

''The connection to Avastin is very remote,'' said Napoleone Ferrara, a Genentech researcher who worked on the study.

''The study showed deletion must take place inside the cells. An extracellular inhibitor like Avastin is not likely to interfere with this process. The study suggested instead that a small molecule is more likely to do so,'' he said.

But he said it is too early to draw conclusions about this new class of drugs based on a genetic study in mice.

In June, Abbott Laboratories Inc. and Genentech said they would collaborate to develop a cancer drug using this approach.

Iruela-Arispe believes angiogenesis inhibitors will continue to be effective weapons in treating cancer but researchers should consider a more targeted way of getting the drug to the tumor.

Currently, Avastin and other such drugs are infused so that they circulate around the patient's entire body.

REUTERS SKB RAI0854