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AZD6244 IS A MUTAGEN FOR RAF GENES

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AZD6244 IS A MUTAGEN FOR RAF GENES Powered By Docstoc
					INTRODUCTIONMany genes play important functions for the normal cell cycle
or program. Whenever there is any problem in normal gene expression or
when these genes are mutated all the mechanisms of cell proliferation,
differentiation of cells and apoptosis which leads to the formation of
cancerous cells. AZD6244 or selumetinib is one of the lethal drugs which
cause mutations in these genes for example RAF, RAS and BRAF genes. This
is a kinase inhibitor, and inhibits activity of MEK. MECHANISM OF
ACTIONAZD6244 is a second generation inhibitor and selective for MAPK/ERK
kinase 1/2. It does not compete with ATP, substrate for these kinases so
it is non-competitive inhibitor. The genes of MAPK/ERK kinase 1/2 are
located downstream to BRAF and RAS and they are efficient activator of
ERK1/2 [2]. AZD6244 is under clinical evaluation phase II trials like
angiogenesis inhibitors. The research on efficacy of this inhibitor has
been done in good number of xenograft models of tumors for example
pancreatic (BxPC3) and colorectal (HT-29) tumor models [2]. It is
reported that 14nmol/L concentration of this drug has ability to inhibit
the activity of MEK1. During in vivo studies, a chronic dose of AZD6244
at 25mg/kg resulted in inhibition of growth in Calu6, colo-205 and SW-620
xenografts. On the other hand acute dose also inhibit the phosphorylation
of ERK1/2. However these results were variable for all these xenograft
models [2]. However this is a selective inhibitor as normal fibroblast
cells are not affected by it. And it was able to suppress the growth of
tumor in case of mouse xenografts [1].EFFECT ON BRAFThose signaling
pathways which are mediated by or through RAF/RAS/MEK/MAP kinases are
having important roles in normal cell growth because the growth is
influenced by different signals of these pathways. In case of cencer cell
lines a large number of mutations are found in RAF and RAS genes. Only a
single mutation in the BRAF gene kinase domain with single single
substitution (V599E) is the cause of abnormal growth of myeloma cells
[4]. Due to these mutations NIH3T3 cells are transformed because of high
kinase activity. Mutated forms of BRAF gene enhance the sensitivity of
cells to inhibition of MEK. Hence those agents which target the mutations
in BRAF genes are able to control the cancerous growth in different cell
lines [3]. It is also studied that these BRAF mutations are connected
with the low expression of protein cyclin D1 thereby arresting cell cycle
at G1 phase. These experimental researchs clearly showed the concept of
tumor growth suppression due to inhibition of MEK1/2. However these
mutations of MEK1/2 can also partially inhibit the tumor induction due to
RAS mutations [3].EFFECT ON ERK1/2AZD6244 has ability to inhibit
phosphorylation due epidermal growth factor (EGF) of ERK1/2 in case of
A431 cell lines, resulting in the growth suppression [4]. This compound
had no effect on normal cell lines while cells having BRAF or RAS
mutations were strongly affected by this inhibitor. These findings
suggested the action of this inhibitor because there was not any other
cytotoxic agent activity. This inhibitor was much more active in case of
SW-620 xenografts which are human based xenografts in nude mice. Research
has been done and it is reported that in case of varyingsly originated
cancer or tumor cell lines; there is no connection between kianse
activity of mutated or phosphorylated protein (MEK/BRAF, RAS and PI3K)
and MEK inhibitory effect [5].CONCLUSIONAZD6244 is a strong inhibitor of
MEK1/2. This inhibitor is undergoing clinical trials and proved to be
effective against cancer cell lines. The downstream genes of different
kinases are inhibited by this agent. However this is not very effective
in some of the cancer cell lines. Hence this agent can be used in
combination with other anti cancer agents like Paclitaxel
andTaxol.REFERENCES1. Yeh TC, Marsh V, et al. Biological Characterization
of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated
Protein Kinase Kinase 1/2 Inhibitor. Clin Cancer Res 2007 March 1;13;
1576.2. Davies BR, Logie A, et al. AZD6244 (ARRY-142886), a potent
inhibitor of mitogen-activated protein kinase/extracellular signal-
regulated kinase kinase 1/2 kinases: mechanism of action in vivo,
pharmacokinetic/pharmacodynamic relationship, and potential for
combination in preclinical models. Mol Cancer Ther 2007 August 6; 2209.3.
Solit DB, Garraway LA, et al. BRAF mutation predicts sensitivity to MEK
inhibition. Nature 2006 Jan 19; 439(7074):358-62.4. Davies H, Bignell GR,
et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jun 27;
417(6892):949-54.5. Dry JR, Pavey S, et al. Transcriptional pathway
signatures predict MEK addiction and response to selumetinib (AZD6244).
Cancer Res 2010 Mar 15; 70(6):2264-73.Related Posts:BIRB 796 : ENHANCES
THE EFFECT OF BORTEZOMIBBELINOSTAT (PXD101) - APOPTOSIS INDUCER OF CANCER
CELLSRelated to AZD6244 (SELUMETINIB) - A MUTAGEN FOR RAF GENES AZD6244
(SELUMETINIB) - CHECKS MUTATIONS IN RAF GENES INTRODUCTION Certain vital
genes are responsible for the maintenance of the normal cell program.
When mutations in these genes get accumulated it disturbs cell
proliferation, ... AZD6244 - REGULATES THE DOWNSTREAM KINASES TO BRAF AND
RAS INTRODUCTION Most of the human tumors are related with the up
regulation of the MAPK pathway. This pathway gets activated as a response
to various ... Selumetinib (AZD6244) - A Unique Molecule with Versatile
Actions and Anti-Tumor Properties INTRODUCTION: RAS-RAF-MEK-ERK pathway
is one of the major deregulated and proliferative pathways which play a
significant role in the pathogenesis of various malignancies.
Approximately 30% ...

				
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