28 november 2004: Bron: Medinews

Leukemia Cells Eradicated in Lab Mice
Medinews.com - December 7, 2004

Scientists have fixed a defect in cancer cells that allows them to avoid the normal cell-death process, and as a consequence, they eliminated leukemia cells from laboratory mice.

With this accomplishment, investigators from the Dana-Farber Cancer Institute (DFCI, Boston, MA, USA) showed that a major anticell death molecule known as BCL-2 is needed by many kinds of cancer cells to survive, and that silencing it with custom-designed drugs may prove to be an effective new method for cancer therapy.

Utilizing pharmacologic agents to influence apoptosis (programmed cell death) in tumors is a new paradigm that hadnt been well explored yet, stated Anthony Letai, M.D., Ph.D., from the laboratory of Stanley Korsmeyer at DFCI. What better way to kill cancer cells than targeting the molecules that directly control their survival?

In the study, lab mice were genetically modified to be highly prone to developing leukemia. The mice were also altered so that the BCL-2 protein could be inactivated by adding an antibiotic to the animals water. The investigators noted that 28 mice, at five to seven weeks of age, had developed leukemia. Fourteen of these mice received the antibiotic in their water to inactivate the BCL-2 genes. Within three days, the treated mice had a reduction in leukemic cells, and their white blood cell counts became normal within 10 days. The study was published in the September 21, 2004, issue of Cancer Cell.

There was no improvement in the untreated mice, whose cancers resisted death because of the active BCL-2 genes. They all died by barely over 200 days, and one of them lived more than one year. The results confirmed an earlier unproven idea that cancer cells could not maintain their malignant characteristics--invading normal tissues, growing out of control, spreading to other areas of the body--in the absence of BCL-2, and furthermore, that suppressing 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, remarked Dr. Letai. The body, through apoptosis, can rid itself of cells that are no longer required or are unessential for embryonic development, or that have sustained damage to their DNA and therefore should not live to reproduce. However in cancer, the self-destruct signals are blocked by proteins belonging to the BCL-2 family. These molecules act as a safeguard on apoptosis, and the cancer cells take advantage of their inhibitory effect by making a surplus of BCL-2 proteins. The death signals, as a consequence, never reach their targets and the cell continues to live on and proliferate uncontrollably.

BCL-2 overexpression has been noted in many types of cancer, and was first found in lymphoma cells. Investigators hypothesized that the overactive BCL-2 might be needed by cancer cells to survive as the apoptosis process tries to destroy the cells, but has not been directly investigated.

This study provides strong support for the speculation that blocking BCL-2 would be lethal to cancer cells. While mice lacking BCL-2 throughout their lives show abnormalities that include altered regulation of their immune response, said Dr. Letai, their survival suggests that treating humans with a BCL-2 inhibiting drug for a definite time period should be tolerable. Agents that block BCL-2 exist but have not been tested in humans; however, the DFCI investigators are now working with a pharmaceutical company on the preclinical development of such an agent.

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