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Choking Off Cancer

New drugs kill tumors from the inside out.

Today’s cancer drugs are notorious for killing healthy cells along with cancerous ones. A new anticancer approach could offer a more precise option: kill just the tumor by choking off its blood supplies. The first drugs based on this approach are now in human trials and, if they work, could provide a virtually side-effect-free means of fighting a host of cancers.

Called vascular targeting agents or antivascular therapies, the new drugs block the blood vessels that carry oxygen and nutrients to tumors. “Basically, it starves the tumor cells to death, so you get a massive amount of tumor-cell kill,” says Dai Chaplin, chief scientific officer at Watertown, MA-based Oxigene. This is in contrast to conventional chemotherapies, which kill cancer cells directly, and to another experimental approach called “anti-angiogenesis,” in which drugs stop new tumor blood vessels from growing.

Oxigene, Aventis and AstraZeneca are each testing vascular targeting agents in humans. These drugs bind to a protein called tubulin, preferentially targeting the tubulin in the cells that line the interior of tumor blood vessels. Long chains of the protein normally form an internal scaffold that helps keep these cells flat. The binding disrupts the scaffolding, and “the cells become fat and podgy and obstruct the blood flow through the tumor,” says vascular-targeting pioneer Phil Thorpe, a professor of pharmacology at the University of Texas Southwestern Medical Center. This effect can be seen within hours after injection of the drug.

So far, researchers have seen very few side effects in human tests, though a number of patients have felt pain in their tumors. And binding to tubulin is short-lived-on the order of hours-long enough to halt tumor blood flow but not long enough to kill normal cells, Thorpe says. “These drugs seem inherently safer than the blanket anticancer drugs that are currently available,” he notes.

Thorpe and other researchers are also developing antivascular therapies that use bioengineered antibodies or other agents to target molecules found only on tumor blood-vessel cells; attached to the antibodies are chemicals that kill the cells or trigger blood clots that block the vessels. Tustin, CA-based Peregrine Pharmaceuticals has licensed Thorpe’s technology and aims to begin human trials in the next year and a half.

“The work that [the researchers] are doing is very good,” says Judah Folkman, a cell biologist at Harvard Medical School and a leader in anti-angiogenesis research. He says that antivascular therapies differ in key ways from the 20-odd anti-angiogenesis drugs now in clinical trials: “Anti-angiogenic therapy targets tiny microscopic vessels in a tumor,” preventing the tumor from growing; “antivascular therapy targets very large vessels and works very quickly.” Some researchers believe this difference will give antivascular drugs an edge in treating large, established tumors.

Ultimately, Folkman and others agree, both approaches will likely be used in combination with conventional cancer treatments-and perhaps with each other-to battle a variety of cancers. “The vascular targeting agents kill the tumors from the inside out,” says Thorpe, but a rim of tumor cells survives. Those cells are the most vulnerable to existing chemotherapies and radiation treatments, and to anti-angiogenic drugs. “The whole goal is really two-part,” says Folkman: reducing the harsh side effects of cancer treatment, and reducing the chance that some cancer cells will evade treatment. “That would be a big step in the next decade, and antivascular therapy will play a major role.”

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