This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project focuses on the mechanism of action of Laromustine, a sulfonylhydrazine anticancer prodrug currently in clinical trials for acute myelogenous leukemia and glioma multiforme. The activity of Laromustine is a function of two reactive electrophiles that are generated upon base-catalyzed activation in situ: a 2-chloroethylating species and methylisocyanate. The 2-chloroethylating species ultimately forms cytotoxic, interstrand DNA crosslinks, and the carbamoylating activity of methylisocyanate synergizes with the 2-chloroethylating activity, resulting in significant cytotoxicity to neoplastic cells. 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, signaling pathways, and cell death mechanisms 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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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Mount Desert Island Biological Lab
Salsbury Cove
United States
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Dickinson, Patsy S; Qu, Xuan; Stanhope, Meredith E (2016) Neuropeptide modulation of pattern-generating systems in crustaceans: comparative studies and approaches. Curr Opin Neurobiol 41:149-157
Dickinson, Patsy S; Calkins, Andrew; Stevens, Jake S (2015) Related neuropeptides use different balances of unitary mechanisms to modulate the cardiac neuromuscular system in the American lobster, Homarus americanus. J Neurophysiol 113:856-70
Morris, Robert L; Pope, Hans W; Sholi, Adam N et al. (2015) Methods for imaging individual cilia in living echinoid embryos. Methods Cell Biol 127:223-41
Farnham, Kate R; Dube, Danielle H (2015) A semester-long project-oriented biochemistry laboratory based on Helicobacter pylori urease. Biochem Mol Biol Educ 43:333-40
Yu, Jeffrey C; Fox, Zachary D; Crimp, James L et al. (2015) Hedgehog signaling regulates dental papilla formation and tooth size during zebrafish odontogenesis. Dev Dyn 244:577-90
Dickinson, Patsy S; Sreekrishnan, Anirudh; Kwiatkowski, Molly A et al. (2015) Distinct or shared actions of peptide family isoforms: I. Peptide-specific actions of pyrokinins in the lobster cardiac neuromuscular system. J Exp Biol 218:2892-904
Dickinson, Patsy S; Kurland, Sienna C; Qu, Xuan et al. (2015) Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system. J Exp Biol 218:2905-17
Gilbert, Andrew S; Wheeler, Robert T; May, Robin C (2015) Fungal Pathogens: Survival and Replication within Macrophages. Cold Spring Harb Perspect Med 5:a019661
McCall, Nora; Mahadevia, Darshini; Corriveau, Jennifer A et al. (2015) Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats. Pharmacol Biochem Behav 132:125-135
Jung, Dawoon; Adamo, Meredith A; Lehman, Rebecca M et al. (2015) A novel variant of aquaporin 3 is expressed in killifish (Fundulus heteroclitus) intestine. Comp Biochem Physiol C Toxicol Pharmacol 171:1-7

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