BioWorld International Correspondent

LONDON - Clinical trials of a cancer treatment that involves giving a genetically modified virus that selectively replicates in cancer cells are expected to begin next year.

A study of the strategy, which involves giving the modified virus in conjunction with a drug that only becomes active when it encounters an enzyme produced by the virus, has shown that it significantly can prolong the survival of mice with bowel tumors.

The method is known as GDEPT, which stands for gene-directed enzyme prodrug therapy. Although the recent work examined the response of a mouse model for bowel cancer, the system could in principle be used for any solid tumor to which the virus can be targeted.

Caroline Springer, professor of biological chemistry at the Institute of Cancer Research in Sutton, UK, told BioWorld International, "For the first time, we have shown that we can achieve significant regression of tumors in a model of human bowel cancer in mice. We have also shown that we can selectively target the tumor - there is a high ratio of the virus in the tumor, compared to other normal tissues."

The study also is important, she noted, because it examines the mechanism by which GDEPT works. "The fact that it works therapeutically is of great interest," Springer said, "but the reasons why it works are also very important."

A phase I trial of the treatment, involving about 30 patients with head and neck cancer, is expected to begin next year.

A paper describing the study appears in the May 17 issue of Cancer Research. Its title is "Suicide gene therapy of human colon carcinoma xenografts using an armed oncolytic adenovirus expressing carboxypeptidase G2." The study was funded by Cancer Research UK and the Institute of Cancer Research.

The concept of delivering an enzyme to a tumor, before giving a harmless "prodrug" that the enzyme would convert into a toxic cancer-killing agent, has been around for about 20 years. First attempts involved targeting the enzyme to the cancer cells using an antibody - the strategy was called ADEPT, for antibody-directed enzyme prodrug therapy. Researchers hoped that activating the prodrug only at the site of the tumor would minimize the side effects of chemotherapy.

GDEPT has been developed to make the strategy more efficient. The idea is to use a virus (instead of an antibody, as in ADEPT) to deliver the gene encoding the enzyme that will activate the prodrug.

For the experiments reported in Cancer Research, Springer and her team capitalized on one major difference between normal cells and cancer cells - the presence or absence of the enzyme telomerase, which helps the cell to maintain its telomeres.

Telomeres are the repetitive strips of DNA found at the ends of chromosomes. In many cells, each time they divide, the telomeres get shorter until eventually they disappear altogether, and the cell enters a pathway leading either to senescence or apoptosis.

The enzyme telomerase helps the cell to maintain its telomeres. Telomerase is not expressed in most adult human cells, but it is active in up to 85 percent of human cancer cells.

Springer and colleagues therefore modified the genome of an adenovirus to include a sequence that, when it came into contact with telomerase, would switch on production of viral proteins. As a result, although the virus could enter most murine cells, it only would replicate in those containing telomerase.

The experimental adenovirus also included the gene for the enzyme carboxypeptidase G2 (CPG2), which selectively converts a prodrug called ZD2767P into a cytotoxic drug. The virus produces CPG2 only when it replicates.

Working with a mouse model of colorectal cancer, the team went on to show that giving the modified virus in conjunction with the prodrug induced a significant delay in growth of tumors.

Further studies showed that giving the prodrug with the modified virus caused cross-linking of DNA in the tumor cells. Such cross-linking prevents the DNA from being separated for synthesis and cell division, and the cells die. There was also a significant "bystander effect," with killed cells inducing uninfected cells nearby to undergo apoptosis, too.

Springer said: "The beauty of our approach is that the cancer cells are made to commit suicide both by the virus and the activated drug - the two work in tandem. And once activated, the drug has the added bonus of causing the virus to produce more of the activating protein, which activates more of the drug, and so on. It's the first time we've seen a positive feedback loop like this in a GDEPT therapy."

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