Digging in the dirt

NOTTINGHAM, U.K.—Scientists at the U.K.'s University ofNottingham and the Netherlands' University of Maastricht are digging deep inthe fight against cancer—and they aren't afraid to get their hands dirty.

Building on decades of research into the drug deliverypotential of a harmless soil-dwelling bacteria, the scientists recentlypresented evidence showing how this strain can specifically target canceroustumors, and ultimately, be used as a vehicle to deliver drugs in frontlinecancer therapy.

Although these findings about the bacteria strain—called Clostridia—have generated quite a bit ofinterest, scientists have been aware of its potential for many years. Clostridia are an ancient group ofbacteria that evolved on the planet before it had an oxygen-rich atmosphere.Because they cannot grow in the presence of oxygen, they produce spores tosurvive.

Medically speaking, Clostridiacannot grow in normal, healthy tissue. Their ability to germinate innecrotic tissue, however, has long been recognized. In the last 50 years, thesecharacteristics have been probed by researchers for their potential to selectand target tumors. In the 1950s, Parker, etal., showed that the injection of Clostridiumhistolyticum spores to the transplanted sarcomas of mice results insignificant tumor lysis. Soon after, it was shown that a direct injection isnot necessary, and that tumor colonization was readily obtained afterintravenous administration of spores.

Now, in a poster that was recently presented at the Societyfor General Microbiology's Autumn Conference at the University of York, theNottingham/Maastricht team has shown it has overcome the hurdles that have sofar prevented this therapy from entering clinical trials. They have introduceda gene for a much-improved version of the enzyme into the C. sporogenes DNA. This improved enzyme can now be produced in fargreater quantities in the tumor than previous versions, and is more efficientat converting the pro-drug into its active form.

"Clostridia areeverywhere—in our soil, in our water, just everywhere," says Nigel Minton, aprofessor of Applied Molecular Microbiology in the faculty of Medicine andHealth Sciences at the University of Nottingham. "When Clostridia spores are injected into a cancer patient, they willonly grow in oxygen-depleted environments, i.e.,the center of solid tumors. Unfortunately, because the outside of the tumor isoxygenated, tumors always regrow. We have done something about that by usingthis enzyme as a pro-drug therapy."

Their approach presents a paradigm shift in the treatmentand control of tumors. Traditional cancer treatments—such as surgery,radiotherapy and chemotherapy—are reasonably successful in controlling thedisease, but in certain types of tumors and circumstances, these approaches maybe ineffective. Moreover, in the cancer community, the holy grail of treatmenthas become the ability to subject tumor cells to a toxic agent while at thesame time excluding normal, healthy tissues from toxic exposure.

In the past 20 years, a significant amount of effort hasfocused on attempting to localize protein-based anti-cancer agents specificallyto the site of tumors. The resulting therapeutic effect is dependent on theclass of protein that is used. These range from proteins that have some directeffect to enzymes that are able to generate a cytotoxic drug from an innocuousprecursor, such as prodrug-converting enzymes.

As we have entered the gene era, focus has switched to thedelivery of the gene that encodes the therapeutic protein, predominantlythrough the use of eukaryotic viral vectors. This approach also presents majorchallenges, 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 relativelyinefficient at being distributed throughout the tumor mass.

However, recent experiments have shown that althoughintravenously injected Clostridia sporesare dispersed throughout the body, only those that encounter the hypoxicenvironment of a solid tumor go on to germinate and multiply. Thispredisposition of Clostridia sporesto germinate selectively in the hypoxic regions of solid tumors makes them anideal delivery vehicle for anti-cancer agents, according to Minton and hiscolleagues.

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, butleave healthy tissue unscathed," he adds.

Ultimately, the Nottingham/Maastricht team hopes thesefindings will lead to a simple and safe procedure for curing a wide range ofsolid tumors. They hope to begin testing this strain in cancer patients by2013.

"A successful outcome could lead to its adoption as afrontline therapy for treating solid tumors. If the approach is successfullycombined with more traditional approaches, this could increase our chance ofwinning the battle against cancerous tumors," says Minton.