Apoptosis is the death of cell in a programmed fashion that is observed largely in multicellular organisms. This programmed cell death occurs in a cascade of biochemical events which include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation and chromosomal fragmentation. Anywhere between 50 and 70 billion cells die each day due to apoptosis in the average human adult. This cascade has been hypothesized to be exploited as an ideal method of anti-cancer strategy traditionally by inducing DNA damage with chemotherapy and radiotherapy.
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These methods have been the backbone of most anti-cancer therapies today, but with increasing knowledge of intrinsic and extrinsic pathways of apoptosis, innovative apoptotic agents have been under investigation since the past several years. There are currently several of these agents in clinical trials for potential role in cancer therapeutics and are expected to become another weapon in our arsenal for the fight against cancer. In technical process death receptors CD95, death receptor DR4 and DR5 along with tumor necrosis factor receptor 1 TNFR1 can effectively induce apoptosis when bound by their ligands. Significant evidence obtained in several animal models confirms the validity of strategies for targeted apoptosis and has revealed an enormous potential for therapeutic intervention in a variety of illnesses. Almost all key participant proteins in cellular apoptosis regulation have been identified and can be targeted by therapeutic strategies which include above mentioned death receptors, Bcl-2 proteins, caspases, endogenous caspase inhibitors and transcriptional regulators.
The current scenario is quite challenging with greater restraints than drivers due to low success ratio. The superior tumor killing activity of TRAIL agonists and the toxic side effects associated with systemic treatment of other death ligands. In animal models a great degree of success was achieved for treatment against inflammatory bowel disease with the help of anti-TNF antibodies or genetic TNF knockout. WHO predicted that annual cancer cases will reach to 19.3 million by 2025 from the 14.1 million annually in year 2012. There were 8.2 million deaths from cancer in the world in 2012 according to cancer research U.K. More than 60% of world’s total new annual cases occur in Africa, Asia and Central and South America. These regions account for 70% of the world’s cancer deaths. This also represents a sizable opportunity for innovative cancer therapeutics companies worldwide. Current economic scenario indicates an improving purchase power and increasing investment in healthcare in developing countries which also governs the fact that emerging players in this arena can profit considerably contrary to conventional observations that profit can be gained only from developed regions such as North America and Europe.
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Current companies that are involved in the research and development of targeted apoptosis therapeutics include Genentech and Amgen are in the process of conducting phase-1 clinical trials for soluble TRAIL agonists as anti-cancer agents. An agonistic TRAIL-R2 antibody (TRA-8) was generated by Sankyo Co., Ltd. (Tokyo, Japan) and proved to be cytotoxic against primary hepatocellular carcinoma cells without inducing cell death in normal hepatocytes. Human Genome Sciences Inc. has recently enrolled patients in phase 2 clinical trials with the TRAIL-R1-specific human monoclonal antibody HGS-ETR1 for the treatment of nonsmall cell lung cancer, colorectal carcinoma, and non-Hodgkin lymphoma. According to the study, approximately six of 57 patients enrolled even reached a stable disease situation. GlaxoSmithKline disclosed a series of similar piperidinyl substituted isatins and related 5-alkylaminosulphonyl-3,3-dichloro-oxindoles. With this, Pfizer has also continued research in caspase inhibitors such as isatin-based caspase inhibitors, from which the compound MMPSI, a (2-methoxymethylpyrrolidinyl)-sulfonylisatin, was able to reduce ischemic injury. This can also be used in targeted apoptosis for cancers. Several Merck inhibitors are currently in preclinical trials.
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