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Researchers eliminate leukemia in mice

Researchers eliminate leukemia in mice, demonstrating potential new approach to cancer drug therapy. New drugs may target molecule blocking normal self-destruction in cancer cells.
Scientists at Dana-Farber Cancer Institute have corrected a flaw in cancer cells that lets them evade the normal cell-death process, and as a result they eliminated leukemia cells from mice. With this achievement, the researchers confirm that a key anti-cell-death molecule called BCL-2 is required by many types of cancer cells to survive, and that silencing it with designer drugs may prove to be an effective new avenue for cancer therapy.

Using drugs to manipulate apoptosis, or "programmed cell death" in cancers "is a new paradigm that hasn't been well explored yet," said Anthony Letai, MD, PhD, in the laboratory of Stanley Korsmeyer at Dana-Farber. "What better way to kill cancer cells than targeting the molecules that directly control their survival?"

Letai is the lead author and Korsmeyer, a Howard Hughes Medical Institute investigator, is the senior author of a report published in the Sept. 21 issue of Cancer Cell. The other authors are Mia D. Sorcinelli and Caroline Beard. The report describes an experiment with laboratory mice genetically modified to be highly prone to developing leukemia. The mice were also modified so that the BCL-2 protein could be turned off by adding an antibiotic to the animals' water.

The scientists observed 28 mice, which, at 5 to 7 weeks of age, had developed leukemia. Fourteen were given the antibiotic in their water to turn off the BCL-2 genes. Within three days, the treated animals had a decline in leukemia cells and their white blood cell counts became normal within 10 days.

There was no such improvement in the untreated mice, whose cancers resisted death because of their active BCL-2 genes: they all died by just over 100 days of age. By contrast, five of the mice with silenced BCL-2 genes survived for over 200 days, and one of them lived more than a year. The findings confirmed a previously untested notion that cancer cells could not maintain their malignant behavior growing out of control, invading normal tissues, spreading to other parts of the body in the absence of BCL-2, and, further, that muzzling that "survival" molecule in cancer cells would allow them to self-destruct.

"This is the first specific evidence that removal of an apoptotic defect by itself can kill cancer in a living organism," said Letai. Apoptosis is a normal quality-control process within cells. In response to signals from their environment or signals from their own internal damage-sensors, a series of molecular interactions cause cells to release a lethal chemical that destroys them. Through apoptosis, the body can rid itself of cells that are no longer needed or are superfluous in embryonic development, or have sustained damage to their DNA and therefore should not live to reproduce.

But in cancer, despite the cells' damaged DNA and other abnormalities, the self-destruct signals are blocked by proteins belonging to the BCL-2 family: these molecules act as a check on apoptosis, and cancer cells take advantage of their inhibitory effect by making an excess of BCL-2 proteins. As a result, the death signals never reach their targets and the cell continues to live on and proliferate uncontrollably.

Overexpression of BCL-2 has been observed in many types of cancer, and was first discovered in lymphoma cells. Scientists speculated that overactive BCL-2 might be required by cancerous cells to survive in the face of the apoptosis process attempting to kill the cells, but the question hadn't been directly tested.

The experimental results provide strong support, the authors wrote, for the theory that blocking BCL-2 would be toxic to cancer cells. While mice lacking BCL-2 throughout their lives show abnormalities including altered regulation of their immune response, said Letai, their survival nonetheless suggests that treating humans with a BCL-2 inhibiting drug for a defined period of time should be tolerable. Drugs that block BCL-2 exist but have not been tested in humans, but Letai and his colleagues are working with a drug company on the preclinical development of such a drug.

The study was funded by grants from the National Institutes of Health, the American Society for Hematology Scholar Award Program, and the Claudia Adams Barr Foundation.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.

Woman to meet Bloomfield marrow donor

His his bone marrow proved an excellent match for a 67-year-old California grandmother

Paul Egan / The Detroit News

BLOOMFIELD HILLS -- Sometimes the small things people do make a huge difference.

That proved true for Roger Winkelman of Bloomfield Hills and Sandra Sholkoff of Woodland Hills, Calif.

Winkelman, 51, a lawyer and father of two who has been a regular blood donor for 30 years, says he doesn't remember when he filled out a card to also register as a bone marrow donor.

But his bone marrow proved an excellent match for Sholkoff, a 67-year-old grandmother who has leukemia and needed a life-saving transplant in 2004.

Winkelman took a required physical examination, received a series of shots and spent a good part of one day at the hospital having bone marrow stem cells extracted from his blood.

"I had no idea who it was going to, or even what state it was going to," he said.

But on Friday, Winkelman and Sholkoff will meet for the first time at the 30th annual bone marrow recipient survivor reunion at City of Hope Cancer Center in Duarte, Calif.

Unlike organ donors, bone marrow donors are able to meet their recipients if both parties agree.

Sholkoff's form of leukemia causes a sharp drop-off in normal blood cell production in the bone marrow, which is the soft jelly-like tissue inside bones. Marrow contains stem cells that are essential to producing healthy blood.

Winkelman, a former treasurer of the Michigan Democratic Party, said it was a highly emotional experience to recently talk on the telephone with Sholkoff for the first time. But he feels he did very little to help produce a magnificent result.

"It's not like I did brain surgery or dove in the water to save this lady's life," Winkelman said. "The doctors and the medical people did all the tough stuff."

Sholkoff, who has returned to work part-time in a medical office, said she is "beginning to get a little anxious" about the meeting. "One of my sons said, 'You have to hold it together when you meet him,'" Sholkoff said. "I said, 'No, I don't have to hold it together.'"

"I'm just very grateful and thankful to Roger and to the doctors and to God," she said. "They saved my life."

Winkelman will attend the reunion with his wife, Linda, who played a role in his donation. It was the blood she lost during childbirth that encouraged him to become a more active donor, he said.

You can reach Paul Egan at (313) 222-2069

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