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Curing cancer in mice

One injection can give a mouse cancer but a second can cure it. That was one of the conclusions made from recent experiments on mice conducted by Steve Kennel and Saed Mirzadeh, both of ORNL's Life Sciences Division.

Dozens of mice were injected with lung cancer or breast cancer cells. The injected cells lodged in the mouse lungs and grew there. Several of the mice were later anesthetized, and the tiny, solid tumors in the lungs were imaged by high-resolution X-ray computed tomography, using the ORNL-developed MicroCAT scanner (see MicroCAT "Sees" Hidden Mouse Defects).

The cancer-stricken mice were then injected with a special monoclonal antibody chemically hitched to a radioisotope produced at ORNL. In this protocol, the antibody targets the blood vessels of each tumor like a smart bomb; the antibody, which is a protein, docks with proteins found in lung blood vessel cells. The radiation from the parked radioisotope destroys the tumor cells around the blood vessel but, remarkably, leaves the vessel intact. Using the MicroCAT scanner, ORNL's Mike Paulus took images of the mice every few days; the images showed the gradual disappearance of the tumors."

"We demonstrated that this technique cures mice of lung tumors," Kennel says. "When we can deliver the radioisotope to the blood vessel that serves the tumor, we can kill the tumor. As a result of this radioimmunotherapy, the life spans of the treated mice are extended dramatically."

By contrast, the mice with implanted cancer cells that were not treated died in 15 days. The mice that received too low a dose of radiation also eventually died of the lung tumors.

Interestingly, the mice that received higher radiation doses were cured of cancer, but died earlier than normal, healthy mice. "These mice lived much longer than the other mice in the experiment, but they eventually died of pulmonary fibrosis," Kennel says. "The reason is that their lungs exhibited an inflammatory response as debris-collecting white blood cells were recruited to the lung to remove the damaged and dead cells."

Other types of experiments in radioimmunotherapy have been performed for years in mice, but the success rate has been low. "Previous approaches for radioimmunotherapy of solid tumors does not work using labeled antibodies that bind directly to tumor cells, because antibody stays in the blood and only a small fraction reaches the cells in the solid tumor," Kennel says. "Our approach has been to select or make a radiolabeled antibody that targets and parks in the blood vessels in the solid tumor. The type of radiation used is an alpha particle emitter that kills every cell within 100 microns."

The researchers found that a targeted antibody labeled with either radioactive bismuth-213 (213Bi) or astatine-211 was most effective. Bismuth-213 is an alpha emitter obtained at ORNL; it is a decay product from the Laboratory's stockpile of uranium-233 left over from its molten-salt reactor experiments in the late 1960s. The astatine-211 used comes from the National Institutes of Health.

Recently, Kennel and a postdoctoral scientist, Sandra Davern, used a bacterial virus engineered to display antibody-like molecules. The bacterial virus was injected into mice with lung tumors. The researchers found that some of the virus stuck to tumor blood vessels. These engineered antibodies were separated by molecular biology techniques from the virus and replicated and amplified in bacteria for use in radioimmunotherapy experiments in mice.

These ORNL successes in eradicating lung tumors in mice could provide important clues about how to achieve effective human cancer cures.



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