The long range objective of this research project is to provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic potential as antitumor agents. Collaborative studies carried out concurrently at Austin (UT) and Kalamazoo (Upjohn) have provided structural information on the CC-1065-DNA adduct as well as insight into the biochemical response to the DNA damage produced by CC-1065. Taken together these results suggest three alternative ways in which CC-1065 may exert its considerable potency as an antitumor agent. During the next project period, we propose to pin-point the molecular basis for the antitumor activity of CC-1065. Our strategy will involve correlation of biological (antitumor) and biochemical activities with structural alterations in the CC-1065-analog-DNA adducts. The three dimensional structural characterization of the CC-1065-DNA adduct and analog complexes will rely upon 1H-NMR (and possibly X-ray crystallographic analysis) studies on the defined CC-1065-oligodeoxyduplex adduct. Biochemical parameters monitored in response to CC-1065-DNA damage include DNA sequence specificity, tele-stability effects, DNA repair consequences and possibly the effects of CC-1065 on gene expression using SV40 DNA. The synthesis of CC-1065 analogs, and their biological evaluation for antitumor activity and toxicity will be conducted in a separate effort funded by The Upjohn Company. The results of this investigation will not only provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic properties, but will provide considerable insight into the mechanisms whereby specific chemical modifications of DNA effect its structure and function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030349-07
Application #
3169229
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1981-07-01
Project End
1988-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78713
Chapman, P B; Houghton, A N (1991) Induction of IgG antibodies against GD3 ganglioside in rabbits by an anti-idiotypic monoclonal antibody. J Clin Invest 88:186-92
Hurley, L H (1989) DNA and associated targets for drug design. J Med Chem 32:2027-33
Hurley, L H; Lee, C S; McGovren, J P et al. (1988) Reaction of CC-1065 and select synthetic analogs with DNA. Biochem Pharmacol 37:1795-6
Warpehoski, M A; Hurley, L H (1988) Sequence selectivity of DNA covalent modification. Chem Res Toxicol 1:315-33
Hurley, L H; Lee, C S; McGovren, J P et al. (1988) Molecular basis for sequence-specific DNA alkylation by CC-1065. Biochemistry 27:3886-92
Tang, M S; Lee, C S; Doisy, R et al. (1988) Recognition and repair of the CC-1065-(N3-adenine)-DNA adduct by the UVRABC nucleases. Biochemistry 27:893-901
Hurley, L H; Boyd, F L (1988) DNA as a target for drug action. Trends Pharmacol Sci 9:402-7
Hurley, L H; Needham-VanDevanter, D R; Lee, C S (1987) Demonstration of the asymmetric effect of CC-1065 on local DNA structure using a site-directed adduct in a 117-base-pair fragment from M13mp1. Proc Natl Acad Sci U S A 84:6412-6
Reynolds, V L; McGovren, J P; Hurley, L H (1986) The chemistry, mechanism of action and biological properties of CC-1065, a potent antitumor antibiotic. J Antibiot (Tokyo) 39:319-34
Needham-VanDevanter, D R; Hurley, L H (1986) Construction and characterization of a site-directed CC-1065-N3-adenine adduct within a 117 base pair DNA restriction fragment. Biochemistry 25:8430-6

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