Greetings,
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)
Genasense
Gossypol
GXO1
ABT-737
~ Karl
==
Drug discovery: Small is beautiful
SOURCE:
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
