It was previously unknown whether cellular senescence or programmed cell death - apoptosis - was the more important safeguard mechanism for suppressing tumours arising from dysfunctional telomeres.

Aged cells have abnormal chromosomes with dysfunctional telomeres - shorter ends - that can promote tumorigenesis in the absence of the tumour suppressor p53, and may be related to the higher incidence of cancer in older individuals. However, in the presence of p53, dysfunctional telomeres can induce a permanent arrest of cell growth, known as senescence. Sandy Chang and colleagues studied mutant mice with dysfunctional telomeres and copies of the p53 gene that cannot initiate p53-dependent apoptosis but can execute p53-mediated senescence.

The authors found that activating the senescence pathway was sufficient to suppress spontaneous tumorigenesis. Their findings suggest that, by halting cellular proliferation, p53-mediated senescence may act as an important tumour suppressor mechanism in aged cells.

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"Chemotherapy is toxic to cancer cells, but the problem is the cells come back so you don't completely eradicate the tumor. One of the main reasons they come back is the tumor already has established an environment which helps protect it, even after chemotherapy," Dr. Mellor says.

Although the IDO inhibitor will first be studied alone, he believes it will become part of the treatment cocktails that are becoming the standard for cancer care, possibly enabling less toxic doses of other drugs to be used.

Another goal for IDO suppression is to treat chronic infections that induce this mechanism, Dr. Mellor says.

"This mechanism is induced by pathogens to protect themselves from host immunity," says Dr. Mellor. "HIV certainly is a potent inducer of this mechanism." He suspects other diligent viruses and bacteria are as well.

"This is obviously an evolutionary adaptation that the pathogen has to protect it from being eliminated by the host," he says. "That is why the infection does not go away. In the case of HIV, we know it persists for decades, and in those decades it's slowly eating away at the immune system so that it becomes unable to deal with the infection. That is where AIDS comes from. The current standard of care for HIV patients is to slow that process, that wearing-down process of the immune system."

In 2002, MCG researchers showed that dendritic cells, which present antigens to T cells, express IDO. "If they express IDO, it's an important control point," Dr. Mellor says of research published in the Sept. 13, 2002 issue of Science.

"IDO has been known for decades," he says. "What was not known was IDO activity was regulating the adaptive immune response."

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