Abstract

The long-term objectives of the proposed research are to understand the unique chemical and biological properties of amino carboxy stabilized radicals and their dimer precursors, to utilize these radicals as reducing agents for determination of the redox chemistry of the anthracycline anti-tumor drugs, and to develop these radicals as rescue agents for high dose adriamycin rescue therapy.
The specific aims are (1) to compare quantitatively the chemical reactivity of various anthracyclines as a potential measure of activity and/or toxicity, (2) to determine the reactivity of intermediate redox states of the anthracyclines and to establish further catalytic roles for the anthracyclines as indicators of biological modes of action, (3) to synthesize and study amino carboxy stabilized diradicals as multiple electron reducing agents for the anthracyclines and water soluble mono-radicals, both as potential rescue agents for adriamycin. The primary biomedical benefits from the proposed research are new knowledge for the design of better anti-tumor drugs and chemotherapy protocols, new drugs and methods for the control of anti-tumor drug toxicity and the development of non-toxic, non-enzymatic, biological reducing agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024665-08
Application #
3166535
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1979-01-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Colorado at Boulder
Department
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309

  Publications

Kato, S; Burke, P J; Fenick, D J et al. (2000) Mass spectrometric measurement of formaldehyde generated in breast cancer cells upon treatment with anthracycline antitumor drugs. Chem Res Toxicol 13:509-16
Taatjes, D J; Fenick, D J; Koch, T H (1999) Nuclear targeting and nuclear retention of anthracycline-formaldehyde conjugates implicates DNA covalent bonding in the cytotoxic mechanism of anthracyclines. Chem Res Toxicol 12:588-96
Taatjes, D J; Fenick, D J; Gaudiano, G et al. (1998) A redox pathway leading to the alkylation of nucleic acids by doxorubicin and related anthracyclines: application to the design of antitumor drugs for resistant cancer. Curr Pharm Des 4:203-18
Taatjes, D J; Fenick, D J; Koch, T H (1998) Epidoxoform: a hydrolytically more stable anthracycline-formaldehyde conjugate toxic to resistant tumor cells. J Med Chem 41:1306-14
Serafino, A; Sinibaldi-Vallebona, P; Gaudiano, G et al. (1998) Cytoplasmic localization of anthracycline antitumor drugs conjugated with reduced glutathione: a possible correlation with multidrug resistance mechanisms. Anticancer Res 18:1159-66
Taatjes, D J; Gaudiano, G; Resing, K et al. (1997) Redox pathway leading to the alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin. J Med Chem 40:1276-86
Taatjes, D J; Gaudiano, G; Koch, T H (1997) Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron. Chem Res Toxicol 10:953-61
Fenick, D J; Taatjes, D J; Koch, T H (1997) Doxoform and Daunoform: anthracycline-formaldehyde conjugates toxic to resistant tumor cells. J Med Chem 40:2452-61
Taatjes, D J; Gaudiano, G; Resing, K et al. (1996) Alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin. J Med Chem 39:4135-8
Gaudiano, G; Koch, T H (1991) Redox chemistry of anthracycline antitumor drugs and use of captodative radicals as tools for its elucidation and control. Chem Res Toxicol 4:2-16

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