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Patients Against Lymphoma


 ASH 2005 Notes: Apoptosis & IAPs

Last update: 12/19/2005

As old-timers among us know, apoptosis is a process by which cells rid themselves of themselves.  Commit suicide.  
For immune cells in particular, apoptosis is essential for the body to achieve the proper balance of cells.   For example, in response to a threat, immune cells activated to kill the invader divide rapidly and go to work.  But when the job is done, they need to go away without causing the body harm.  The mechanism for this is apoptosis.  The apoptosis event is called a cascade, because one signal activates another, and still another, until the cell extinguishes itself in a way that is not disruptive to the body.
In many lymphomas a defect in a gene and other defects, cause too much production of specific proteins (such as BCL-2) that interrupt or block the apoptosis cascade.    These proteins are called inhibitors of apoptosis proteins (or IAPs, for short).
Okay, this is old news, but it was stunning to observe the illustrations of the cascade and just how much detail on this process - and where it can go wrong or be interrupted in cancer cells - has been discovered and chronicled. 
The cellular system is intricate, and the discovery of the system is awesome.  But most importantly, the insights are already leading to new drugs to treat cancer cells in a highly specific way.   That is, by interrupting the interruptions of the apoptosis cascade.  (IIAPs, if you will.) 
IAPs lead to cell survival and tumor formation in cancer cells, but also to drug resistance. Most drugs kill cancer cells by inducing damage that activates apoptosis. The proteins within the cells that interrupt this process result in resistance to treatment.   
IAPs are attractive treatment targets because their inhibition does not appear to be toxic to normal cells, at least in animal models.
Identifying targets that are specific to cancer cells is the first step.  The second is designing drugs that have high affinity for the target (fit well), and that can also get to the target without being changed.  Hydrocarbon stapling, for example, enables molecules to expand and snap into place after they enter cells.  (presumably, Un-stapled, they may not penetrate to the target.)
Some new molecules that target IAPs follow, along with an article on one of them (ABT-737)
~ Karl
Drug discovery: Small is beautiful


By using nuclear magnetic resonance (NMR) and structural studies, researchers have discovered a small-molecule inhibitor of the pro-apoptotic proteins BCL-XL and BCL2, which causes the regression of established tumors and improves survival in mice.

When overexpressed, the anti-apoptotic proteins BCL-XL and BCL2 contribute to tumour initiation, progression and resistance to therapy. Using nuclear magnetic resonance (NMR) and structural studies, Rosenberg and colleagues have now identified a small-molecule inhibitor of BCL-XL and BCL2, which causes the regression of established tumours and improves survival in mouse models.

Full story: http://www.signaling-gateway.org/update/updates/200506/nrc1636.html
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