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Early studies show attenuated bacteria stop growth of tumor cells
Years from now, medical practitioners may look back at this spring as a landmark in the race to find a cure for cancer. Human trials are expected to begin in the coming weeks on tumor-targeting altered salmonella bacteria engineered by Yale researchers in New Haven, CT. The research is funded by Vion Pharmaceuticals, also of New Haven.
Researchers "de-fanged" the bacteria by disabling the salmonella gene for the powerful toxin lipopolysaccharide so it would not cause food poisoning and the potentially life-threatening reaction it can trigger in the human body.
Researchers found the altered salmonella slowed the growth of melanoma tumors in mice and later in a variety of malignant tumors in pigs.
"The discovery has changed all our lives," says John Paweleck, PhD, senior research scientist at Yale’s dermatology department, and David Bermudes, PhD, Vion’s associate director of biology and adjunct assistant professor at Yale.
Paweleck, Bermudes, and their research team made the discovery while experimenting with bacteria as a delivery system for a variety of anti-cancer agents, since researchers have long thought certain bacterial infections seem to help cancer patients survive longer. The bacteria were then implanted subcutaneously in mice with melanoma tumors. What they discovered was "tremendously exciting," Paweleck says.
The bacteria spread through the circulatory system and multiplied, stunting tumor growth within 24 hours but not triggering the extreme white cell alarm reaction responsible for the septic shock that kills organisms infected with wild salmonella.
"Salmonella seeks out cancers in the body. It travels through the blood stream and finds any tumor, even those too small for us to know about," says Bermudes. "That is its beauty. We don’t have to target a specific location since it can even seek out small tumors which are metastasizing."
"Salmonella loves tumors," says Paweleck. "It seeks out a safe harbor in tumors; places with little circulatory systems which typically escape drug therapy."
Paweleck and Bermudes think the salmonella slows tumor growth in part by competing with malignant cells for the essential nutrient, adenine. They also theorize the suppression may be due to the salmonella’s stimulation of the immune system, among other possibilities.
In early trials, mice with melanoma tumors in the control group died within four weeks, but the salmonella-inoculated mice lived three to four weeks longer. Later studies in pigs found similar results with malignant breast, lung, and colon tumors.
Current generations of the salmonella strain are keeping the mice alive five times longer than the control group, and Bermudes says the second generation is expected to be more potent with an even smaller dose of the bacteria.
Paweleck says they observed no side effects, a stark contrast to the common side effects of other treatments — nausea, weight and hair loss.
"You can inject a 20-pound pig with 109 salmonella cells, and the animal wouldn’t even notice it," Paweleck says.
Usually reserved researchers are enthusiastic about the development.
"We have high hopes in this area. I am watching it closely," says Debabrata Banerjee, PhD, a molecular pharmacologist at Memorial Sloan-Kettering Cancer Center in New York City.
Banerjee says the laboratory work and animal trials on the altered salmonella have been "very thorough," and he laid to rest his early fears that the salmonella might revert to its toxic state.
Bermudes admits the team was concerned about its reversion during early trials, but it hasn’t happened.
"Even if it did get out of control, salmonella poisoning is easily treated with a wide variety of antibiotics," he says.
Vion expects FDA approval for Phase I trials in the first quarter of 1999, Bermudes says.
The trials will focus on patients with mela-noma who will be given one injection of altered salmonella and monitored over a period of time. Later trials will likely include colon and breast cancers, he says.
For more information, John Paweleck can be reached at (203) 785-3078, and David Bermudes can be reached at (203) 498-4210.