Salmonella as a new weapon against cancer?
Scientists have developed a strain of salmonella that is no longer pathogenic and has specifically multiplied in cancer cells in animal experiments. They want to equip the bacteria with anti-cancer genes and use them as a kind of Trojan horse against tumors. A genetically engineered strain of Salmonella may be able to target cancerous tumours, multiply within the tumours, and inhibit tumor growth. Scientists at Yale University School of Medicine and their colleagues report in the journal Cancer Research this intriguing use of a bacterium that, when unmodified, can cause wild-type food poisoning and septic shock. According to John M. Pawelek, Ph. D., associate professor of pharmacology at Yale, the modified Salmonella are able to target solid tumors in experimental animals, even though the bacteria are no longer pathogenic. At the same time, there are few or no side effects.
Indeed, explains Dr. Pawelek, we can now significantly extend the life of mice that have melanomas by injecting them with our engineered bacteria. Although less than ten wild-type bacteria are enough to kill a mouse, we can inject ten million cells of our attenuated strain without the mice showing any symptoms of infection. After the Salmonella got into the bloodstream of the mice, they tracked down tumors, multiplied there in large numbers and dramatically slowed down the tumor growth rate. The researchers do not yet understand the exact mechanism. However, the treated mice lived longer than the control group. Since the Salmonella multiply directly in the tumor itself, anti-tumor genes that were genetically engineered into the bacteria are also multiplied there.
John M. Pawelek, David Bermudes, and K. Brooks Low of Yale School of Medicine co-invented this radical new cancer therapy and worked hand-in-hand with a team of scientists from Vion Pharmaceuticals, Inc. The stated aim is to to prepare the modified Salmonella for possible clinical testing on cancer patients.
The story of discovery began five years ago: oncologist Pawelek, parasitologist Bermudes and geneticist Low began working together on this project in late 1992. At the time, Bermudes was interested in Pawelek's work, particularly an old theory that metastatic cells that spread throughout the body behave in a similar way to white blood cells. After a few weeks, Bermudes came to Pawelek with a new idea: he wanted to use parasites specific to white blood cells to detect cancer cells. They tested several parasites for their ability to infect human melanoma cells in culture. Her further work soon focused on Salmonella, which also affects human melanoma cells in a culture.
The researchers turned to Low because of his expertise in bacterial genetics. In his laboratory, they developed salmonella within weeks, which could serve as a harmless weapon against cancer. A few months later they received the first data from animal experiments. In December 1995, Vion Pharmaceuticals entered into a licensing agreement with Yale, filed a patent application and hired Bermudes as principal scientist. Now, several years later, the Yale-Vion data were presented at the American Association for Cancer Research conference in San Diego last April and released on October 15.
The results of Rakesh K. Jain and his colleagues at Harvard University make it clear how important the work of the three scientists is. Using engineering methods, they had shown that there are numerous physical barriers within tumors that prevent effective treatment with anticancer drugs. Pawelek explains: "Tumors are supplied with blood irregularly, whereby the blood vessels do not reach many regions. You tend to be under pressure from within. Jain's group and others have shown that this property creates a barrier that prevents viruses, antibodies and drugs from reaching the innermost parts of tumors. Salmonella, which can move by their own swimming motion, are less subject to these physical barriers. They can therefore penetrate into deeper areas and multiply there. In particular, when Salmonella is endowed with anti-cancer genes, it has the ability to destroy tumor cells in areas where other therapeutic agents cannot easily reach.
Most exciting is the potential use of our technology for cancer therapy in humans," the three scientists agree. "We've made salmonella both safe and effective for laboratory animals, and now the challenge is to do the same to do for people. The safety issue appears to be under control and potential efficacy appears very promising.
The Heidelberger Verlag Spektrum der Wissenschaft is the operator of this portal. Its online and print magazines, including "Spektrum der Wissenschaft", "Gehirn&Geist" and "Spektrum – Die Woche", report on current research findings.
