Although the patients died, the experiment was a success _demonstrating for the first time that gene therapy can halt theprogression of severe lung cancer in humans. The experimentaltreatment also proved powerful enough to temporarily force thedisease into remission.

Doctors from the University of Texas M.D. Anderson Cancer Centerin Houston, carried out the pioneering study, by injecting gene-bearing retroviruses directly into lung tumors.

"We regard this as `proof of principle,'" said oncologist Jack Roth, amember of the research team. "It shows that you can alter the geneticcomplement of a cancer cell, reprogram the genes in that cancer celland restore normal gene function."

FDA guidelines for the experiment only permitted doctors to treatone tumor site in each patient. All of the men ultimately died ofmetastases that were not injected with the novel therapy, according toa report in the September Nature Medicine.

Autopsies later showed, however, that gene therapy temporarilyhalted tumor growth in three of seven men and brought aboutremissions in three others. One man remained tumor free at theinjection site for the remaining four months of his life. Two othersremained tumor free at the injection sites until their deathsapproximately two months later.

All of the cancers had previously survived conventional treatments,including radiation and chemotherapy.

The doctors used a gene called p53, which was inserted into harmlessbut infectious retroviruses. Sometimes referred to as the guardian ofthe cell, this gene represents a supreme example of self-sacrifice forthe good of the organism.

When a cell begins the wild replication that marks the birth of atumor, p53 ordinarily switches on and stops the cell from replicating_ or even instructs it to commit suicide, a phenomenon known asapoptosis.

Sometimes cells dodge p53's biochemical bullets, by deleting ormutating the twin copies that lie within most cells. Fully half of alltumors are populated with cells that lack functional copies of p53.

Roth and his co-workers decided to see what would happen if theyinserted working copies of p53 into burgeoning tumors. They hopedthat the doctored viruses would infect cells in the tumors and inneighboring tissues, delivering their payloads of working p53 genes.

Preliminary trials of the strategy in laboratory-grown cancer cells andin animal experiments proved promising. In the human study,biopsies of the treated tumors also showed evidence of activeapoptosis, Roth and his colleagues said.

In some cases, killed cancer cells outnumbered the estimatedpopulation of cells infected with the p53-carrying virus.

"What we're actually seeing is regression of tumor that exceeds whatwe would expect," Roth told BioWorld Today.

One More Time? Maybe Not

The finding suggests that virus-infected cells may also be capable ofkilling off adjacent cancer cells. However, a nearly completedclinical trial of p53 gene therapy at the University of PennsylvaniaMedical Center in Philadelphia, has failed to reproduce this effect.

But the University of Pennsylvania trial involves patients withmesothelioma, which emerges in the lining of the lungs and chestcavity. The gene-bearing viruses were applied topically, rather thaninjected into the tumor. These technical differences could account forthe absence of the so-called "bystander effect," Roth said.

Despite this uncertainty, John Minna and Adi Gazdar, of the HamonCenter for Therapeutic Oncology Research at the University of TexasSouthwestern Medical Center in Dallas, call the report a milestone inthe effort to develop effective gene therapy. It also vindicates"translational research" _ the practice of applying laboratoryfindings in clinical settings, they commented in the same issue ofNature Medicine.

At the very least, Roth and his colleagues said they have succeeded intheir Phase I study's modest aim _ demonstrating that the techniqueis safe in humans.

The researchers plan to treat a total of 48 lung cancer patients withp53. They also plan to test the gene therapy approach in 54 peoplewith head and neck cancer.

Some of these patients will receive p53 that has been inserted into thevirus employed by the Pennsylvania team. This microbe is a memberof the cold-causing adenovirus family. The success of this virus innature makes it a promising vector for gene therapy because it infectscells so efficiently, Roth said.

"We are working with the National Cancer Institute to apply thistechnique to other types of tumors, including brain, breast, bladder,ovarian and liver cancer. Because p53 is mutated in all commoncancers, they could provide targets for this type of approach," hesaid. n

-- Steve Sternberg Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.

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