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Digging in the dirt
NOTTINGHAM, U.K.—Scientists at the U.K.'s University of Nottingham and the Netherlands' University of Maastricht are digging deep in the fight against cancer—and they aren't afraid to get their hands dirty.
Building on decades of research into the drug delivery potential of a harmless soil-dwelling bacteria, the scientists recently presented evidence showing how this strain can specifically target cancerous tumors, and ultimately, be used as a vehicle to deliver drugs in frontline cancer therapy.
Although these findings about the bacteria strain—called Clostridia—have generated quite a bit of interest, scientists have been aware of its potential for many years. Clostridia are an ancient group of bacteria that evolved on the planet before it had an oxygen-rich atmosphere. Because they cannot grow in the presence of oxygen, they produce spores to survive.
Medically speaking, Clostridia cannot grow in normal, healthy tissue. Their ability to germinate in necrotic tissue, however, has long been recognized. In the last 50 years, these characteristics have been probed by researchers for their potential to select and target tumors. In the 1950s, Parker, et al., showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumor lysis. Soon after, it was shown that a direct injection is not necessary, and that tumor colonization was readily obtained after intravenous administration of spores.
Now, in a poster that was recently presented at the Society for General Microbiology's Autumn Conference at the University of York, the Nottingham/Maastricht team has shown it has overcome the hurdles that have so far prevented this therapy from entering clinical trials. They have introduced a gene for a much-improved version of the enzyme into the C. sporogenes DNA. This improved enzyme can now be produced in far greater quantities in the tumor than previous versions, and is more efficient at converting the pro-drug into its active form.
"Clostridia are everywhere—in our soil, in our water, just everywhere," says Nigel Minton, a professor of Applied Molecular Microbiology in the faculty of Medicine and Health Sciences at the University of Nottingham. "When Clostridia spores are injected into a cancer patient, they will only grow in oxygen-depleted environments, i.e., the center of solid tumors. Unfortunately, because the outside of the tumor is oxygenated, tumors always regrow. We have done something about that by using this enzyme as a pro- drug therapy."
Their approach presents a paradigm shift in the treatment and control of tumors. Traditional cancer treatments—such as surgery, radiotherapy and chemotherapy—are reasonably successful in controlling the disease, but in certain types of tumors and circumstances, these approaches may be ineffective. Moreover, in the cancer community, the holy grail of treatment has become the ability to subject tumor cells to a toxic agent while at the same time excluding normal, healthy tissues from toxic exposure.
In the past 20 years, a significant amount of effort has focused on attempting to localize protein-based anti-cancer agents specifically to the site of tumors. The resulting therapeutic effect is dependent on the class of protein that is used. These range from proteins that have some direct effect to enzymes that are able to generate a cytotoxic drug from an innocuous precursor, such as prodrug-converting enzymes.
As we have entered the gene era, focus has switched to the delivery of the gene that encodes the therapeutic protein, predominantly through the use of eukaryotic viral vectors. This approach also presents major challenges, as viral vectors exhibit a general lack of specificity for tumors, and once they have been delivered to the site of the tumor, they are relatively inefficient at being distributed throughout the tumor mass.
However, recent experiments have shown that although intravenously injected Clostridia spores are dispersed throughout the body, only those that encounter the hypoxic environment of a solid tumor go on to germinate and multiply. This predisposition of Clostridia spores to germinate selectively in the hypoxic regions of solid tumors makes them an ideal delivery vehicle for anti-cancer agents, according to Minton and his colleagues.
Clostridia, Minton notes, is a "totally natural phenomenon," which requires no fundamental alterations and is "exquisitely specific."
"We can exploit this specificity to kill tumor cells, but leave healthy tissue unscathed," he adds.
Ultimately, the Nottingham/Maastricht team hopes these findings will lead to a simple and safe procedure for curing a wide range of solid tumors. They hope to begin testing this strain in cancer patients by 2013.
"A successful outcome could lead to its adoption as a frontline therapy for treating solid tumors. If the approach is successfully combined with more traditional approaches, this could increase our chance of winning the battle against cancerous tumors," says Minton.