| Description |
Selenium-containing compounds have been studied extensively for their cancer chemo-preventive properties. Although many of these drugs, such as sodium selenite or 1,4-phenylenebis(methylene)selenocyanate(p-XSC), have shown promise as anticancer agents, the toxicity of such compounds limits their usefulness. A selenocysteine prodrug is proposed to supply selenium in a less toxic manner by utilizing selenocysteine beta-lyase to provide selenium in a biochemically available form. This prodrug approach would overcome the instability and potential toxicity associated with selenocysteine alone, but allows slow release of the active component to proved chemoprevention. A novel prodrug of selenocysteine, 2-oxoselenazolidine-4-carboxylic acid (OSCA), was synthesized and preliminary biological data collected utilizing Chinese hamster lung fibroblast cells. Toxicity data collected on both the L- and D- isomers of OSCA showed a significant reduction in cytotoxicity as compared with the parent compound, selenocysteine. OSCA was also less toxic than other selenium-containing compounds such as sodium selenite, sodium selenite, selenomethionine and p-XSC. Studies were conduced to determine if OSCA released the active component, selenocysteine. Enzymatic hydrolysis studies of OSCA with 5-oxoprolinase were attempted, but were not successful. Additionally, non-enzymatic studies were carried out and compared with the sulfur-containing compounds, 2-thiazolidine-4-carboxylic acid (OTCA). As expected OSCA showed no significant hydrolysis under physiological condition, much like OTCA. Finally, glutathione peroxidase induction (GSH-Px) was studied to determine if OSCA provided selenium in a biochemically available form. The results were compared to sodium selenite and p-XSC. Neither L- or D-OSCA showed induction of GSH-Px in preliminary studies. In conclusion, these studies provide evidence that prodrug forms of selenocysteine can reduce toxicity commonly associated with selenium-containing compounds. However, further investigation is warranted to determine their effectiveness at providing selenium for protein synthesis or other metabolic pathways that may provide cancer chemo-preventive effects. |
