BioWorld International Correspondent

LONDON - Clusters of synthetic molecules can deliver a potent genetic therapy to tumors in laboratory tests, researchers working in Scotland showed. In preclinical models, the treatment caused tumors of the cervix and bowel to shrink and in some cases disappear altogether.

A bonus is that the delivery molecules themselves have turned out to have considerable anticancer effects, comparable to some standard cancer chemotherapy drugs. Another is that it will be possible to adapt the delivery system to deliver other anticancer genes to tumors.

In the longer term, scientists also are likely to explore whether the strategy could be modified to deliver "good" copies of faulty genes to specific tissues in order to treat a range of inherited diseases.

Andreas Sch tzlein, head of experimental therapy and gene medicine at the Cancer Research UK Centre for Oncology and Applied Pharmacology at the University of Glasgow in Scotland, told BioWorld International:

"One of the challenges of cancer therapy, and of gene therapy in particular, is to be able to give a treatment systemically, which will then have its effect specifically on the tumor cells. You have to have something that is quite stable and will not be broken down in the blood, which will then release its cargo when it reaches the tumor. That is a difficult balance to strike, but it looks like the molecule we have used does this quite well."

The University of Glasgow is in the process of forming a spinout company to exploit the discovery and is seeking partners to help the group take their work forward.

Their latest results are reported in the Sept. 18, 2005, issue of Cancer Research in a paper titled "Synthetic Anticancer Gene Medicine Exploits Intrinsic Antitumor Activity of Cationic Vector to Cure Established Tumors."

Sch tzlein's group has been working with star-shaped polymers - so-called dendrimers - to manufacture stable nanoparticles containing DNA. They have been working with a type of molecule that is about 20 times smaller than conventional cationic polymers of the types routinely used in the laboratory.

To date, much gene therapy work has focused on using genetically manipulated viruses to deliver genes to specific types of cell. But Sch tzlein said nonviral systems have many advantages: They are simple, and they can be cheap to make. They comprise a positively charged carrier material, and a negatively charged "cargo" - usually DNA.

"One problem, however, has been that non-viral particles have the reputation of not being efficient enough," he said. "So we wanted to find out if our particles, which we have called Synfect, could deliver a gene efficiently when given systemically into the blood stream, and whether levels of the gene would be high enough to be therapeutically useful."

The team chose to use the gene encoding tumor necrosis factor alpha (TNF-alpha). The powerful cytokine is a potent cancer therapy, but also potentially toxic when given systemically.

Sch tzlein and his colleagues therefore had to find a way to ensure that TNF-alpha was produced or released only inside cancer cells. Their strategy was to couple the gene to a promoter that would turn on manufacturing of the protein only in cells expressing the enzyme telomerase.

Telomerase is expressed in up to 90 percent of cancer cells, but not usually in normal cells. The cancer cells need it in order to keep on dividing. In that case, when they give the signal to make telomerase, the genetic material contained in the dendrimer responds by making TNF-alpha.

"One of the striking things about this was how well it worked," Sch tzlein said. The researchers found that the therapy was effective in various laboratory models of human tumors. In some types, 80 percent of the tumors disappeared after one week of treatment and did not recur during the 17-week period of the study.

The other striking feature of the study was that the dendrimer alone had significant antitumor effects.

"We have compared it with doxorubicin and similar conventional chemotherapy agents, and we found that it was as potent and probably safer than these drugs," Sch tzlein said.

Future work will focus on identifying other genes that could be delivered usefully to tumors using this system, and which tumors will respond best to that approach.

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