8 April 2003 17:20 GMT

by Henry Nicholls

Bacteria that thrive in the anaerobic conditions found at the core of many tumors can be genetically tweaked to carry chemotherapeutic agents directly into tumor tissue, claim microbiologists. If current research goes to plan, the strategy could enter clinical trials within two years.

While the success of conventional chemo- or radiotherapy continues to improve, the enduring drawback of these diffuse treatments is the side effects they have on healthy tissue, including nausea, hair loss, a weakened immune system, sterility, and sometimes even death.

There have been considerable efforts to destroy cancer cells directly, but these have encountered problems, says Nigel Minton, professor of infections and immunity at Nottingham University, UK. "People have been having difficulty in specifically targeting enzymes to tumor cells," he told BioMedNet News.

By contrast, a species of the bacterial genus Clostridium is showing considerable promise at focusing treatment solely on cancer cells. "It's very specific, provided the tumor has a low oxygen or necrotic center," said Minton. "There are certain tumors that are very difficult to treat, such as brain tumors, which it may be used to treat," he said.

"This represents a new treatment modality for cancer," said Ivan King, vice-president of research at Vion Pharmaceuticals in Connecticut, USA. But King echoes Minton's caution that this system could not be used to treat all types of tumor: "One of the major limitations for Clostridia is that it only localizes in large tumors," he said. "Small tumors, including metastases, probably because of the presence of oxygen or the absence of an anaerobic center, will be resistant to this treatment," he added.

The search for a 'magic bullet' treatment that will home in on its target has centered around two main approaches, says Minton. One idea has been to fuse a key enzyme to an antibody that has been raised against a tumor-specific antigen. However, because different tumors carry different antigens, and some carry none at all, this antibody-based bullet frequently missed its mark and was complex to manufacture.

"Then," said Minton, "people have jumped on the idea of using gene therapy." But the virus vectors that would carry the therapeutic genes tend not to be specific to cancer cells, he says. Although they can be injected straight into the tumor, they don't spread well to all the cells.

Minton's strategy, which he and collaborators in five European laboratories are currently developing for clinical trials, uses a non-pathogenic species of bacterium, Clostridium sporogenes, that has been transformed to express an Escherichia coli enzyme, cytosine deaminase.

The patient receives these engineered Clostridium spores intravenously, which germinate after about a week, but only under the anaerobic conditions at the heart of the tumor. Then, a non-toxic and inactive "prodrug" - 5-fluorocytosine (5-FC) - is injected, and circulates around the body. This is converted by the E. coli cytosine deaminase being expressed by the Clostridia to 5-fluorouracil (5-FU), a powerful cytotoxic agent that is used in conventional chemotherapy.

"We have shown ... that in an animal model, you can get tumor regression using a certain combination of enzyme and prodrug," said Minton, who presented his data yesterday at the Society for General Microbiology annual meeting in Edinburgh, UK.

Whether this can be repeated in clinical trials remains to be seen. "There's bound to be safety issues in any system where you're using a living organism," he conceded. "We are building in additional safety measures, but that's something I wouldn't want to talk about because it might be patentable."

But Sandra Nuyts, an experimental radiologist at the Catholic University in Leuven, is not so hung up on matters of safety. "The use of this apathogenic bacteria is safe," she said. "No immune responses are known, the bacteria can be eradicated by giving the proper antibiotics, no gene insertion in the host genome is required."

In spite of its promise, Nuyts says that using bacteria to fight cancer may only be one part of an overall treatment package. "I do not believe that the bacteria alone will be capable of curing cancer," she said. "You will need to combine this therapeutic modality with another modality like radiotherapy or chemotherapy to eradicate all tumor cells," Nuyta concluded.