In Vivo Use of GST-activated Nitric Oxide Donors to Treat Cancer and the Multidrug Resistance Phenotype

A class of enzymes known as Glutathione-S-Transferases (GSTs) is over expressed in many forms of leukemia and solid tumors. This over expression is a major mechanism whereby malignant cells acquire drug resistance. Nitric oxide (NO) is a major biologic effector that inhibits tumor cell growth. A major problem with widespread in vivo use of NO is its non-specific action on non-cancerous cells including its effects on vascular tissue resulting in hypertension. This invention defines a number of compounds of the diazeniumdiolate family that release NO upon activation by GST. Prior to activation, these chemically inert prodrugs are non-toxic and do not produce any vasoactive effects in vivo. However, once inside malignant cells expressing high levels of GST, these compounds are ezymatically cleaved to deliver toxic levels of NO to the cells. At the same time, the released NO inhibits further GST activity thereby reducing drug resistance within the cells. One lead diazeniumdiolate compound, known as JS-K, displays significant in vitro and in vivo antineoplastic activity comparable with other clinical chemotherapeutics.

Benefits
Cancer is recognized as the second most common cause of death in the developed world, and can arise as a result of a number of factors. This has the potential to be used in many types of cancers. Worldwide the market for cancer therapeutics is more than $20 billion.

Stage of Development
A published international patent application (PCT/US03/08877) has been filed.
This technology is part of an active and ongoing research program and has been demonstrated to work in proof-of-concept experiments which include a working prototype and is entering into pre-clinical development. It is available for developmental research support or licensing under either exclusive or non-exclusive terms.

Additional Info
*Saavedra JE, et. al. �Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: in vitro antileukemic activity.� J Med Chem.43(2): 261-9, 2000.
*Shami, PJ, et. al. �JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity.� Mol. Cancer Ther. 2: 409-17, 2003.

Inventor(s): Paul Shami

Type of Offer: Licensing



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