Of mice and men


A shrinking tumor. Courtesy EntreMed, Inc.

resume speed
  shrinking tumorGreat results from natural blood vessel inhibitor
Endostatin, the naturally occurring chemical that inhibits the growth of blood vessels, not only shrank the mouse tumors -- it also caused them to become "dormant," so that even after the researchers withdrew treatment, the tumors sat idle.

That's big.

Writing in Nature last November, a research group that included Michael O'Reilly of the Dana Farber Cancer Center in Boston, and Judah Folkman, a Harvard Medical School professor who has spent 30 years championing the study of new blood vessels in cancer, described the decline and disappearance of three types of human tumors. (See "Anti-angiogenic Therapy..." in the bibliography.)

Remember, this breakthrough -- if that's what it is -- concerns mice, not people.

Still, endostatin did a monster job on three human cancers growing in the mice. Endostatin was given in cycles: Small amounts of the protein caused the tumors to shrink to barely visible size. The researchers then halted the drug treatment and did not resume it until the tumors had grown to more than 1 percent of the animal's body weight.

A recipe for resistance
Giving a drug in such an on-off cycle is a recipe for stimulating drug resistance, a huge problem in conventional cancer chemotherapy. Drugs that work at first lose effectiveness over time because cancer cells divide rapidly and sloppily, forming lots of mutants. If any of these mutants resist the drug, they divide and form a drug-resistant line of cancer cells. (Similarly, bacteria can evolve resistance to antibiotics.)

Yet no resistance arose to endostatin. Every time the mice received the blood vessel inhibitor, their tumors shrank as rapidly as after the first dosage.

The lack of resistance is easy to explain: Angiogenesis occurs when genetically stable endothelial cells in the blood vessels divide to build new blood vessels, and it is those cells that the inhibitor affects. Because it is not affecting the mutating tumor cells directly, the inhibitor can sustain its effectiveness. "The tumor cells could mutate and develop resistance, but it will be more difficult for the endothelial cells to do so," explains James Mixson, a research assistant professor at the University of Maryland School of Medicine. Mixson is trying to use genetic therapy to stimulate production of anti-angiogenesis factors in mice.

But with chemotherapy, resistance did arise: When O'Reilly's group gave a conventional anti-cancer drug to mice with aggressive lung cancer, the drug controlled the tumors for 13 days, after which they resumed growing. Such resistance accounts for a common tragedy. Cancer patients benefit at first from chemotherapy, then the drug loses potency over time.

More good news
An apparent victory over resistance was remarkable enough, but the researchers found something equally exciting: After two, four, or six treatment cycles, the tumors stopped growing -- even after endostatin was withdrawn. As the researchers wrote, "Tumors remained dormant at a barely visible size while the animals were observed for 103 to 165 more days after the beginning of the dormant state." (Since each mouse day equals 35 human days, that's the equivalent of 10 to 16 human years.) Despite repeated use, no resistance arose to endostatin

Furthermore, while it's not possible to assess all side effects in mice, the overall signs were positive. As the researchers wrote, "All endostatin-treated mice in each tumor system remained healthy and gained weight normally."

There is no accepted explanation for this dormancy. Perhaps the drug leaves a residual "capsule" of angiogenesis inhibitor around the tumor. Alternatively, it may cause programmed cell death in tumor cells. Nor is it clear why a chemical that inhibits blood vessel growth would cause tumors to actually shrink, as endostatin did.

These results, combined with increasing scientific acceptance of Folkman's view that angiogenesis plays a key role in cancer, sparked the recent flood of attention to angiogenesis inhibitors. Many desperate cancer patients called doctors, only to learn that human trials of the most promising inhibitors are one to two years away, and there's no guarantee that they will work in people. (History, as we'll see shortly, argues that "magic bullets" for cancer are highly unlikely.)

A long struggle for acceptance
It was in 1971, around the time when President Richard Nixon declared "war" on cancer, that Folkman first began arguing that tumors can't grow to a dangerous size until they form their own blood supply. Almost every tissue in the body gets blood from the thinner-than-a-hair capillaries that lace our tissues. Most cells actually touch the capillaries, through which nutrients, oxygen, and various signaling molecules diffuse into the cells.

But tumors start out without circulation, and thus are limited to the trickle of nutrients that can diffuse from the nearest capillary.

At first, many scientists ridiculed Folkman's assertion that tumors secrete chemicals that cause blood vessels to grow. Folkman was unable at first to test his hypothesis because it was impossible to isolate the faint chemical growth signals, so he spent decades building his scientific case.

Now, precise biochemical techniques have proven him right, and made his angiogenesis hypothesis the accepted wisdom in cancer research. At least 11 anti-angiogenesis drugs are being tested in clinical trials, including thalidomide, the notorious baby-deformer once sold as a sedative. Although few results have been announced, three drugs have proven effective enough to be in the last phase of clinical trials against pancreatic, lung, breast and prostate cancers.

In contrast, endostatin and angiostatin, the two powerful, naturally-occurring inhibitors, have yet to be tested in people. Indeed, the researchers have had a hard time making enough to treat mice, let alone humans.

Which brings us to the central question: Should we believe the mice experiments? Or is this just another "cancer cure" that's destined to fail when tested against the real thing -- aggressive human cancers?


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