Acylfulvenes, derivatives of illudin natural products, are a promising class of drugs for cancer treatment. They are notable for high therapeutic indices and selectivities for tumor cells, and clinical trials are underway. Acylfulvenes are alkylating agents, but the detailed chemical mechanisms of DNA and protein-adduct formation, and how this relates to tumor-cell selectivity is not known. The long-term goals of this project are to define a mechanistic paradigm accounting for the selective toxicities of acylfulvenes that will lead to the development of combined-agent and tailored therapies designed to site-specifically tune acylfulvene toxicity. The objectives of this application are to establish a link from acylfulvene bioactivation to biomolecular target modification and cytotoxicity.
The specific aims are to (1) Characterize in vitro patterns of DNA alkylation by acylfulvenes and distinguish adducts that result from direct modification of DNA from those of bioactivation-coupled reactions;(2) Characterize the mechanism of inhibition of cellular redox proteins by acylfulvenes;(3) Determine the influence of a bioactivating reductase on acylfulvene alkylation reactions and toxicity in cells. The research approach for aim 1 involves the synthesis of chemically activated molecular probes that will be used to identify products of DNA alkylation by bioactivated acylfulvenes. We will use chemical characterization methods to identify the structures of acylfulvene DNA adducts.
In aim 2, we will use enzyme-inhibition studies combined with a mass-spectrometry-based approach to structurally map protein covalent modification.
In aim 3, we will use reductase-overexpressing cells and stable tumor cell lines to test the impact of adduct formation in the complex environment of the cell. Acylfulvenes are a new class of drugs that kill cancer cells by becoming covalently linked to biomolecules in the cell and initiating a sequence of biological events that result in cell death. The initial chemical transformations that govern this process and how they differ in cells that are sensitive to acylfulvenes versus those that are not are unknown. The ability to selectively target tumor cells is a central problem in cancer therapy and consequently understanding this mechanism is important for designing safer cancer therapy strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123007-05
Application #
8101215
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2007-04-23
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2011
Total Cost
$178,096
Indirect Cost
Name
Swiss Federal Institute of Tech (Eth Zurich)
Department
Type
DUNS #
481907673
City
Zurich
State
Country
Switzerland
Zip Code
8092
Erzinger, Melanie M; Bovet, Cédric; Uzozie, Anuli et al. (2015) Induction of complementary function reductase enzymes in colon cancer cells by dithiole-3-thione versus sodium selenite. J Biochem Mol Toxicol 29:10-20
van Midwoud, Paul M; Sturla, Shana J (2013) Improved efficacy of acylfulvene in colon cancer cells when combined with a nuclear excision repair inhibitor. Chem Res Toxicol 26:1674-82
Pietsch, Kathryn E; van Midwoud, Paul M; Villalta, Peter W et al. (2013) Quantification of acylfulvene- and illudin S-DNA adducts in cells with variable bioactivation capacities. Chem Res Toxicol 26:146-55
Tanasova, Marina; Plutschack, Matthew; Muroski, Megan E et al. (2013) Fluorescent THF-based fructose analogue exhibits fructose-dependent uptake. Chembiochem 14:1263-70
Yu, Xiang; Erzinger, Melanie M; Pietsch, Kathryn E et al. (2012) Up-regulation of human prostaglandin reductase 1 improves the efficacy of hydroxymethylacylfulvene, an antitumor chemotherapeutic agent. J Pharmacol Exp Ther 343:426-33
Erzinger, Melanie M; Sturla, Shana J (2011) Bioreduction-mediated food-drug interactions: opportunities for oncology nutrition. Chimia (Aarau) 65:411-5
Liu, Xiaodan; Pietsch, Kathryn E; Sturla, Shana J (2011) Susceptibility of the antioxidant selenoenyzmes thioredoxin reductase and glutathione peroxidase to alkylation-mediated inhibition by anticancer acylfulvenes. Chem Res Toxicol 24:726-36
Pietsch, Kathryn E; Neels, James F; Yu, Xiang et al. (2011) Chemical and enzymatic reductive activation of acylfulvene to isomeric cytotoxic reactive intermediates. Chem Res Toxicol 24:2044-54
Dahlmann, Heidi A; Vaidyanathan, V G; Sturla, Shana J (2009) Investigating the biochemical impact of DNA damage with structure-based probes: abasic sites, photodimers, alkylation adducts, and oxidative lesions. Biochemistry 48:9347-59
Norton, Jolanna; Matsuo, Hiroshi; Sturla, Shana J (2009) Synthesis of deoxytetrahydrouridine. J Org Chem 74:2221-3

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