This project focuses on the mechanism of action of Cloretazine, a sulfonylhydrazine anticancer prodrug currently in clinical trials for acute myelogenous leukemia (Vey and Giles, 2006) and glioma multiforme (Badruddoja et al., 2007). These efforts will also include the nitrosoureas, a related class of compounds that are actively used in the clinic (Gnewuch and Sosnovsky, 1997). The activity of Cloretazine is a function of two reactive electrophiles that are generated upon base-catalyzed activation in situ: a 2-chloroethylating species and methylisocyanate (Finch et al., 2001; Shyam et al., 1996). The 2-chloroethylating species ultimately forms cytotoxic, interstrand DNA crosslinks (Baumann et al., 2005; Penketh et al., 2000), and the carbamoylating activity of methylisocyanate synergizes with the 2-chloroethylating activity, resulting in significant cytotoxicity to neoplastic cells (Baumann et al., 2005; Baumann et al., 2004). These in situ chemical processes are similar to those of other anticancer compounds, including nitrosoureas. This project will involve an investigation of several enzymes as targets likely to be modified with a carbamoyl group from methylisocyanate so as to explain the synergistic cytotoxicity. In addition, the effects of exposure to studied agents on gene expression and signaling pathways will be elucidated. The proposed research will greatly enhance the understanding of the relationship between the chemical reactivity of these compounds and their observed pre-clinical and clinical effects, which potentially could lead to more effective chemotherapeutic strategies.
Recent Publications and Presentations
- Paine AN, Praggastis VA, Dale LE, Tepper JL, Reichelderfer B, and Rice KP “Cell death mechanisms associated with the carbamoylating activity of the anticancer prodrug Laromustine.” 2010 Colby Undergraduate Research Symposium.
- Bellairs J, Lapointe CP, and Rice KP “Effects of Laromustine on the expression of genes controlled by the transcription factor AP-1.” 2010 Colby Undergraduate Research Symposium.
- Paine AN, Praggastis VA, Dale LE, Tepper JL, Reichelderfer B, and Rice KP “Cell death mechanisms associated with the carbamoylating activity of the anticancer prodrug Laromustine.” 101st Annual meeting of the American Association for Cancer Research, April 17-21, 2010, Washington, DC.
- Praggastis, V Alexandra; and Rice, Kevin P (2010) Small-molecule Inhibitors of DNA Base Excision Repair. In: ENCYCLOPEDIA OF LIFE SCIENCES 2010, John Wiley & Sons, Ltd: Chichester [DOI: 10.1002/9780470015902.a0022212].
- Frederick AM, Davis ML, and Rice KP (2009) “Inhibition of human DNA polymerase ß activity by the anticancer prodrug Cloretazine”, Biochem Biophys Res Commun. v378. pp. 419-423.Rice KP, “The consequences of carbamoylating activity with anticancer sulfonylhydrazines” Northeast Regional IDeA Meeting, August 6, 2009, Whitefield, NH.