Nitric Oxide Metabolism Plays a Crucial Role in Visual Pattern Memory in Drosophila

Bioreductively-Activated Prodrugs of Nitric Oxide (NO) Harinath Chakrapani and Kavita Sharma Indian Institute of Science Education and Research, India Approximately one-third of human tumours contain areas with limited oxygen tension (hypoxia) in comparison with normal cells. As oxygen is a potent radiosensitizer, hypoxic tumours are often less responsive to radiation treatment. Due to diminished and chaotic blood supply, hypoxic areas are poorly accessible to cancer drugs and hence chemotherpeutics also have diminished efficacy in shrinking hypoxic tumours. Furthermore, therapy selects for cells that have a highly invasive and malignant phenotype with increased angiogenesis further complicating treatment of hypoxic tumours. Together, these effects lead to higher levels of treatment failures in tumours with significant areas of hypoxia and hence, developing new strategies targeting hypoxic cancer cells is necessary. Nitric oxide (NO) is a potent chemical radiosensitizer and has been shown to synergize with radiation to promote apoptosis in hypoxic cells. Tumoristatic activity of NO has been demonstrated by both in vitro and in vivo studies. Furthermore, NO is an inhibitor of hypoxia inducible factor (HIF-1), which enhances blood vessel growth and increases glycolytic enzymes in hypoxic cells. Finally, due to its diffusible nature, nitric oxide can in small amounts penetrate cells leading to enhancement in cytotoxic effects. Thus, NO is a potential drug candidate for targeting hypoxic tumours. Here, we report our results pertinent to the design, synthesis and evaluation of prodrugs of nitric oxide that can be used to selectively target cancer cells which over-express bioreductive enzymes such as DT-diaphorase. Our initial evaluation shows that these compounds may have therapeutic potential against cancers that over-express this enzyme.