Genasense® (oblimersen sodium) Injection is a drug that inhibits the production of a protein known as Bcl-2. By reducing production of Bcl-2 in cancer cells, Genasense® treatment seeks to restore the basic biological process whereby cancer cells can be readily killed by treatment with current methods of anticancer therapy. This process is known as programmed cell death or apoptosis. There are several key features that underlie Genta's approach to cancer treatment with Genasense®. Genta's clinical trials programs focus on treating cancer patients with Genasense® along with the administration of anticancer therapy with the intention of potentiating the cancer-killing effects of treatment.
Genasense® (oblimersen sodium) Injection Development Strategy
Genta is developing Genasense® (oblimersen sodium) Injection with the intention of potentiating the cancer-killing activity of standard anticancer therapies. In a typical example, Genasense® might be administered for several days and then be immediately followed by regular doses of chemotherapy. This sequence would then be repeated, depending upon the particular type of chemotherapy regimen and indication. In other applications, Genasense® might be administered concurrent with or after conventional chemotherapy, again depending on the chemotherapy and indication. Genasense® has the potential to be used in combination with most types of anticancer therapy.
TECHNOLOGY
Genasense® reduces the expression of Bcl-2 protein by a technology known as Antisense. This technology is based on synthetic molecules that are designed to reduce the level of only a single protein previously identified as a therapeutic target. Vitrually any gene can be targeted by Antisense molecules. We are focusing on Bcl-2 because it is one of the most consistently validated target genes in the history of oncology research.
Genasense® (oblimersen sodium) Injection Advantage: • Scientific proof of principle for antisense technology • Targets a critical protein that is highly expressed in most types of cancer • Completed Phase 3 clinical trials with clearly identifed responsive patient populations
A more detailed description of Antisense can be found in Technologies.
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Bcl-2 Protein Bcl-2 is a normal human protein expressed in a narrow range of cell types and at specific times during tissue formation. Bcl-2 and related protein family members play a pivotal role in the normal process of cell death (known as apoptosis). Aged cells throughout the body constantly undergo apoptosis in order to accommodate the billions of new cells produced daily. Apoptosis can occur before the end of a normal cell life span when damage to the cell occurs. The regulation of this process—i.e., the decision to initiate the process of cell death—is mediated primarily by the Bcl-2 protein family.
Bcl-2 is normally found localized to the outer membrane of an intracellular organelle called the mitochondria. The presence of the Bcl-2 protein on the surface of the mitochondrial membrane prevents the release of a substance known as cytochrome c from inside the mitochondria into the cell. Release of cytochrome c from the mitochondria triggers apoptosis by activating a number of enzymes (known as caspases) which ultimately result in programmed cell death.
Most chemotherapies induce the types of cellular damage that causes apoptosis to occur (first panel below). The damage causes cell death signals to reach the mitochondria, which in turm releases cytochrome c and activates caspases that mediate cell death. Bcl-2 overexpression in tumor cells, and the presence of Bcl-2 protein on the mitochondrial membranes, does not prevent cell death signals from reaching the mitochondria. However, the Bcl-2 protein prevents the release of cytochrome c. Thus the apoptotic process is shut down (second panel below). Treatment of cells with Genasense® reduces Bcl-2 protein levels. This restores the ability of the mitochondria to release cytochrome c and initiate the caspase activation cascade. Thus, the ability for the cells to undergo apoptosis in response to chemotherapy is restored (third panel below).
View the Bcl-2 Mechanism of Action Video Windows Media Player is needed to view this animation
The image below describes the proportion of patients who at the time of diagnosis overexpress Bcl-2 relative to a normal cellular population.
Bcl-2 is known to: - Prevent programmed cell death (apoptosis) - Enhance metastatic potential of tumor cells - Promote resistance to anticancer therapies - Indicate poor prognosis in many cancer indications
Bcl-2 Link to Cancer High levels of Bcl-2 are associated with most types of human cancer. In preclinical studies Bcl-2 has been shown to block the release of cytochrome C which would ordinarily be triggered by cancer therapy. Bcl-2 also appears to be a major contributor to both inherent and acquired resistance to current anticancer treatments.
Genasense® (oblimersen sodium) Injection , Genta’s most advanced anticancer drug, is intended to inhibit the production of Bcl-2, thereby potentially restoring the potential for tumor cells to undergo apoptosis, thus enabling the cancer cell to be killed when treated with current, state of the art cancer therapies.
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