United Press International - September 25, 2002
Ed Susman, UPI Science News

The virus bit -- a protein called "Tat" -- from HIV helps to slide a key receptor blocker into cancerous cells, making it easier for anticancer drugs to destroy them, explained J. William Harbour, associate professor of ophthalmology at the Washington University School of Medicine in St. Louis.

Harbour and colleagues developed the HIV protein molecule and its tag-along cancer fighter after studying the mechanisms of cells in certain eye cancers.

"We have identified a key molecular feature of eye cancers that prevents the cancer cells from dying," Harbour told attendees at a symposium sponsored by Research to Prevent Blindness, of New York City.

The finding led the researchers along a path to a new concept in fighting the disease:

-- First they noted a key gene, p53, whose protein suppresses the growth of tumors, is turned off by an inhibitor in the cancer called HDM2. HMD2 ensures the survival of the cancer cell by defending against attacks by p53.

-- When the cancer cell overproduces the p53-blocking HDM2, however, a cascade starts that results in programmed cell death, a process called apoptosis.

-- The researchers isolated a small fragment of p53 that can attach to HMD2 and prevent the inhibitor from turning off p53's normal function.

-- By flooding the cell with the therapeutic protein molecule, doctors thought p53 would be able to attack the cancer, but they were stymied as to how to get the tiny p53 fragment into the cell. Then along came Tat.

Harbour said Tat is the protein that allows HIV to penetrate into cells, permitting the killer virus to create copies of itself and eventually destroying a person's immune system. However, he said, Tat -- by itself -- isn't harmful.

So researchers took the p53 fragment that blocks HMD2 and attached it to Tat.

The Tat protein enters the cell, dragging the hitchhiking p53 fragment with it.

In laboratory experiments, Harbour said as soon as the Tat-anti-HMD2 combination molecule enters the cancer cell, it binds to HMD2, freeing p53 molecules to initiate the apoptosis cycle. Cancer cells begin dying within hours.

In other laboratory tests with animals, tumors treated with Tat-anti-HMD2 were 95 percent destroyed within three days, while tumors in rabbits treated with a Tat-sham molecule were unaffected.

"That showed us that it was the anti-HMD2 that was working to kill the cells and not the Tat protein," Harbour said. He said that the small portion of the HIV molecule used in the treatment would not result in HIV infection.

"It is amazing how we are using molecular techniques to fight these types of cancer," said Pamela Sample, professor of ophthalmology at the University of California at San Diego. She predicted more and more uses of molecular science will find their way into therapeutic practice.

Harbour suggested the initial findings represent "a proof of principle that the molecular characteristics of eye cancers can be used to design novel therapeutic molecules with potent efficacy and specificity for cancer cells."

In his experiments, the Tat-anti-HMD2 molecule showed effectiveness against retinoblastoma and uveal melanoma cancers that occur in the eye. However, Harbour hinted the concept used in his experiments might be applicable in many other cancers. Because the Tat-anti-HMD2 molecule is so different an approach to fighting cancer, he said, the malignant cells might be unable to find a way to develop resistance against it.

David Beebe, professor of ophthalmology at Washington University, said that intense scientific study of HIV created "resulted in the spinoff of Tat because it has this unusual property of getting into cells. It really points out the importance of basic science."

The small bit of HIV protein would not trigger AIDS in patients being treated for cancer nor would it likely even show up in common tests for HIV infection, Beebe said.
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