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Telling Cells to Die: Apoptosis Research Takes Off

Mike Miller

An increased understanding of the signals and pathways that regulate apoptotic cell death is hastening the development of chemotherapeutic interventions to control cancer and other diseases affected by these pathways. With the recent cloning of what is thought to be the eleventh and final enzyme that helps regulate apoptosis, the field may now be headed for exponential growth.

"Seventy percent of major medical illnesses can be linked to apoptotic pathways where too little or too much cell death is taking place," said John C. Reed, M.D., Ph.D., scientific director, Burnham Institute, La Jolla, Calif. Reed noted that on an average day, 70 billion cells are eradicated in a human body, and defects in this eradication process can cause cells to accumulate genetic lesions and lead to genomic instability, resistance to immune attack, and chemoresistance.



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John C. Reed, M.D., Ph.D., scientific director of the Burnham Institute in La Jolla, Calif., noted that "the huge jump in the number of abstracts on apoptosis signals is only the beginning of the search for useful interventions and possible therapies."

 
In the 1970s, pathologists first noted that radiation and chemotherapy could induce morphological features in cells similar to those that had undergone normal apoptosis. Scientists are just now finding out how the activation of apoptotic stimulatory pathways and inhibition of anti-apoptotic pathways can affect survival chances for patients undergoing chemotherapy.

John A. Hickman, Ph.D., Institut de Recherches Servier, Suresnes, France, suggested that it was a paper in Nature in 1988 that showed that genetics could control survival and thus kicked off the initial acceleration of research in the field of apoptosis. By the end of 1999, researchers looking at cell death and survival had been able to ascertain that about 11,000 mutations per cell would probably lead to tumor formation.

"We now believe that in order to address this number of mutations, cells must increase survival signaling, increase tumor suppressors, and modulate their survival threshold to deal with this large amount of mutations," Hickman said.

Nancy Thornberry, Ph.D., Merck Research Laboratories, Rahweh, N.J., said at the April meeting of the American Association for Cancer Research in San Francisco, Calif., that in less than a decade’s time, scientists have found all 11 human caspases, enzymes that are thought to play a major role in apoptosis. Thornberry noted that caspases are important in apoptosis because they have unique recognition systems for macromolecular substrates that they help break down at a pivotal point in the cell death process.

The regulation of the caspase cascade has several layers or phases. In diseases affected by neurodegeneration, therapeutic targets are being aimed at the inhibitory phase of apoptosis, whereas in cancer, scientists are targeting the activation phase of apoptosis. "We need to have a much better understanding of how capsases are activated in cells before we can find agents that will really affect cancer," Thornberry said.

Anyone who thinks that affecting apoptotic pathways will be a simple task should take a quick look at the huge number of posters and abstracts presented at AACR on apoptosis. Even in those studies looking only at the initiation phase of apoptosis, molecular targets that affect granzyme B cytotoxicity, survival signaling, stress signaling, TNF-family death receptors, and Bcl-2 family ligands were all discussed as possible intervention points. As Reed noted, "the huge jump in the number of abstracts on apoptosis signals is only the beginning of the search for useful interventions and possible therapies."



             
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