These excerpts taken from the SNTA 10-K filed Mar 20, 2008.
Elesclomol Mechanism of Action
Elesclomol is a novel, injectable small molecule that we believe rapidly and potently induces the generation of ROS in cancer cells, increasing the level of oxidative stress in cancer cell and ultimately leading to cancer cell death by apoptosis (programmed cell death).
ROS is a collective term used to describe chemical species that are produced as byproducts of normal oxygen metabolism and include superoxide, hydrogen peroxide, and the hydroxyl radical. In normal cells, ROS are produced at low levels and are effectively neutralized by the cells' antioxidant system. In contrast, cancer cells produce elevated levels of ROS due to their increased metabolic activity, resulting in oxidative stress. Sustained levels of ROS that exceed the cells' antioxidant capacity can readily induce cell death by apoptosis. We believe that oxidative stress is one of the most fundamental differences between cancer cells and normal cells, and that this difference causes cancer cells to be particularly vulnerable to agents that can selectively elevate ROS.
We believe the evidence that the primary mechanism of action of elesclomol is through induction of ROS is strong. This evidence includes:
Once ROS levels in cancer cells exceed the breaking point, cell death occurs through apoptosis from the intrinsic mitochondrial pathway. Apoptotic cell death through the mitochondrial pathway involves the oxidation of cardiolipin, release of cytochrome c from the mitochondria, and activation of the caspase cascade. By increasing ROS and activating the intrinsic mitochondrial apoptosis pathway, we believe that in addition to inducing apoptosis as a single agent, elesclomol can enhance the anti-cancer activity of other chemotherapeutic agents that act through the same pathway. We have shown in preclinical in vivo models that elesclomol significantly enhanced the anti-tumor activity of paclitaxel, rituximab, and gemcitabine, while adding minimal additional toxicity. These results have been demonstrated in a variety of animal models of cancer, including breast, lung, lymphoma, colorectal, cervical carcinoma and melanoma.
Our preclinical safety studies showed that the addition of elesclomol added little or no toxicity to that seen with paclitaxel alone, and that elesclomol has a relatively high therapeutic index, or margin between effective dose and toxic dose. We believe that the favorable safety profile that has been observed preclinically and clinically with elesclomol is due to the pronounced difference between cancer cells and normal cells in their respective ability to recover from such an increase in oxidative stress.
Elevated oxidative stress is one of the most fundamental features that differentiates cancer cells from normal cells. By taking advantage of this fundamental difference, we believe elesclomol offers the potential for a novel anti-cancer approach that is broadly effective across cancer types in conjunction with ROS-sensitive chemotherapeutics such as paclitaxel, while maintaining an attractive safety profile.
Elesclomol Mechanism of Action
Elesclomol is a novel, injectable small molecule that we believe rapidly and potently induces the generation of ROS in cancer cells, increasing the level of
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