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===ABT-737===
===ABT-737===


In the mid-2000s, Abbott Laboratories developed a novel inhibitor of Bcl-2, Bcl-xL, and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI), which target these Bcl-2 family proteins, but not A1 or Mcl-1. It has so far been proven effective in lymphoma or other blood cancer therapies. ABT-737 does not directly induce apoptosis; it enhances the effects of the death signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines. Also, in animal models, it improves survival, causes tumor regression, and results in the cure of a high percentage of mice (1). This compound works so well because, unlike previous BCL-2 inhibitor compounds, ABT-737 binds with higher affinity to Bcl-2, Bcl-xL, and Bcl-w. In in vitro studies, primary cells from patients with B-cell malignancies are extremely sensitive to ABT-737 (2).
In the mid-2000s, Abbott Laboratories developed a novel inhibitor of Bcl-2, Bcl-xL, and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI), which target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors because this compound has higher affinity for Bcl-2, Bcl-xL, and Bcl-w. In in vitro studies, primary cells from patients with B-cell malignancies are extremely sensitive to ABT-737 <ref></redf>. ABT-737 does not directly induce apoptosis; it enhances the effects of the death signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines. In animal models, it improves survival, causes tumor regression, and results in the cure of a high percentage of mice <ref></ref>. Finally, in preclinical studies utilizing patient xenografts, ABT-737 has shown efficacy for treating lymphoma and other blood cancers <ref></ref>.

(1) "An inhibitor of BCL-2 family proteins induces regression of solid tumors." Nature.
2005. 435: 677-681.

(2) Volgler, M., D. Dinsdale, MJ Dyer, and GM Cohen. "Bcl-2 Inhibitors: Small Molecules
with a Big Impact on Cancer Therapy." Cell Death Differentiation. 2009 Mar;16(3): 360-67. National Center for Biotechnology Information. U.S. National Library of Medicine, 19 Sept. 2008.


===ABT-199===
===ABT-199===

Revision as of 18:04, 5 December 2013

Template:PBB Bcl-2 (B-cell lymphoma 2), encoded by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis).[1][2]

Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas. Bcl-2 orthologs[3] have been identified in numerous mammals for which complete genome data are available. The two isoforms of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as 1G5O/1GJH, exhibit similar fold. However, results in the ability of these isoforms to bind to the BAD and BAK proteins, as well as in the structural topology and electrostatic potential of the binding groove, suggest differences in antiapoptotic activity for the two isoforms [4]

Role in disease

Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.

Cancer occurs as the result of a disturbance in the homeostatic balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. But simultaneous over-expression of Bcl-2 and the proto-oncogene myc may produce aggressive B-cell malignancies including lymphoma.[5] In follicular lymphoma, a chromosomal translocation commonly occurs between the fourteenth and the eighteenth chromosomes—t(14;18) — which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.[6] This decreases the propensity of these cells for undergoing apoptosis.

Apoptosis also plays a very active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.[7] The autoimmune disease, type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells are the most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. Researchers have found that mice containing dendritic cells that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal dendritic cells.[7] Other studies have shown that the lifespan of dendritic cells may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[7]

Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.[8] There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[8]

Further research into the family of Bcl-2 proteins will provide a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis[citation needed]. An understanding of the mechanisms involved may help develop new therapies for treating cancer, autoimmune conditions, and neurological diseases.

Diagnostic use

Antibodies to Bcl-2 can be used with immunohistochemistry to identify cells containing the antigen. In healthy tissue, these antibodies will react with B-cells in the mantle zone, as well as some T-cells. However, there is a considerable increase in positive cells in follicular lymphoma, as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining in biopsies may be significant for the patient's prognosis or likelihood of relapse.[9]

Targeted therapies

Bcl-2 inhibitors include :

Genasense

An antisense oligonucleotide drug Genasense (G3139) has been developed by Genta Incorporated to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the protein from being formed.

It was shown that the proliferation of human lymphoma cells (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.[10]

These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial was launched in 2004[11]

By the first quarter 2010, Genasense had not received FDA approval due to disappointing results in a melanoma trial. Although safety and efficacy of Genasense have not been established for any use, Genta Incorporated still claims on its website that studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.

ABT-737

In the mid-2000s, Abbott Laboratories developed a novel inhibitor of Bcl-2, Bcl-xL, and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI), which target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors because this compound has higher affinity for Bcl-2, Bcl-xL, and Bcl-w. In in vitro studies, primary cells from patients with B-cell malignancies are extremely sensitive to ABT-737 Cite error: A <ref> tag is missing the closing </ref> (see the help page).. Finally, in preclinical studies utilizing patient xenografts, ABT-737 has shown efficacy for treating lymphoma and other blood cancers Cite error: There are <ref> tags on this page without content in them (see the help page)..

ABT-199

A Phase Ia trial is currently ongoing to study the effects of agent, ABT-199, a so-called BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia.[12]

January 17, 2013 The study had suspended participant recruitment per a temporary hold [13]

Others

Interactions

Overview of signal transduction pathways involved in apoptosis.

Bcl-2 has been shown to interact with RAD9A,[15] BAK1,[16][17] Reticulon 4,[18] Bcl-2-associated X protein,[15][16][19][20] Caspase 8,[21][22] BECN1,[23] SOD1,[24] Bcl-2-interacting killer,[25][26] BH3 interacting domain death agonist,[25][27] RRAS,[28] C-Raf,[29] BCL2L11,[25][30][31] BNIPL,[32][33] HRK,[25][34] PSEN1,[35] BMF,[36] BNIP2,[32][37] BNIP3,[37][38] Nerve Growth factor IB,[16] BCL2-like 1,[16][39] Myc,[40] BCAP31,[41] SMN1,[42] CAPN2,[43] PPP2CA,[44] Noxa,[25][45] Cdk1,[46][47] TP53BP2,[48] Bcl-2-associated death promoter[25][49] and IRS1.[50]

Human BCL-2 genes

BAK; BAK1; BAX; BCL2; BCL2A1; BCL2L1; BCL2L10; BCL2L13; BCL2L14; BCL2L2; BCL2L7P1; BOK; MCL1; LGALS7 (Galectin-7)

See also

References

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