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Stanford Report, April 12, 2000

Oxygen-shy bacteria deliver treatment to tumors  

BY KRISTIN WEIDENBACH

Cancerous tissue is typically oxygen-starved, a feature that has presented hurdles to effective anticancer treatment. But Stanford researchers are examining this anomaly in a new light and turning a problem into a solution for cancer treatment.

Researchers in the laboratories of J. Martin Brown, PhD, professor of radiation oncology, and Amato Giaccia, PhD, associate professor of radiation oncology, are soliciting the help of oxygen-shy bacteria to transport an anticancer gene therapy product deep into the heart of the tumorous mass. They believe that the microbes will provide a means to deliver the gene therapy medicine exactly where it is needed without having to inject it directly into the tumor. "We're giving the anti-cancer drug essentially only to the tumor," said Brown.

The key to their new technique is a species of bacteria that detests the oxygen that is life-sustaining for humans and many other plant, animal and microbial species. These bacteria are members of the class of anaerobic bacteria, which thrive in the absence of oxygen. They have been used experimentally by anticancer researchers because they can be injected intravenously into humans but they will grow only in the low-oxygen environment deep within a tumor; they are harmless to the rest of the body.

Brown and Giaccia are using Clostridium sporogenes as their vehicle to transport a gene therapy product into a solid tumor. The researchers added an extra gene to the bacteria, forcing them to manufacture an enzyme called cytosine deaminase. The enzyme, in turn, activates a nontoxic pro-drug, converting it into a potent anticancer drug. The nontoxic pro-drug is 5-fluorocytosine and the active anticancer drug is the common chemotherapeutic agent 5-fluorouracil, or 5FU.

"At the moment there's no systemic way of delivering gene therapy - everyone's just sticking needles into the tumor." He believes that injecting substances directly into the tumor is problematic because some tumors are not easily accessible; and, more importantly, the treatment only will be effective at a single site and will not reach tumors that have spread to other parts of the body. The bacteria, on the other hand, will seek out the cancer cells wherever they take up residence and deliver their gene therapy product.

Rather than injecting the bacteria themselves, the researchers infuse hibernating bacterial spores. When the spores reach the tumor they "hatch" into bacteria that begin growing. "We inject the bacteria as spores. They don't do anything unless they meet a tumor and the anaerobic conditions in the tumor, then they start to grow as regular bacteria and make the proteins they're genetically primed to make -- the enzyme we've stuck into them," Brown said.

The research conducted to date has been carried out in mice, but the researchers believe that the bacteria are highly specific gene delivery vehicles that eventually can be used for human cancer therapy. "It looks very promising," said Giaccia.

Within one day of injecting the clostridial spores the enzyme that activates the anticancer drug can be detected in the tumor, according to Brown. Evidence of the enzyme was not found in a large survey of normal mouse tissues, confirming that the bacteria were growing exclusively in the cancerous tissue. More importantly, the researchers found that the mouse tumors began to shrink soon after delivery of the bacteria/pro-drug combination.

Solid tumors are characterized by a decreased amount of oxygen because the blood vessels that supply them typically have abnormal architecture. Compared with the regular, ordered network of arteries and veins in normal tissues, blood vessels in tumors are often highly abnormal. Their walls have no muscle tone and the blood moves sluggishly through the vessels. The cancer cells use oxygen faster than it can be supplied by the defective vessels, leading to areas of dead and dying, oxygen-depleted tissue. And this is just the type of environment that C. sporogenes prefers.

Brown and Giaccia presented their findings at the American Association for Cancer Research meeting in San Francisco, which ran April 1 through 5. Shie-Chau Liu, PhD, and Toru Shibata in Brown's lab are co-authors of the study. SR