Abstract

The bleomycins are a family of antitumor antibiotics used for the treatment of squamous cell carcinomas and malignant lymphomas. Although clinically effective, various bleomycins have exhibited pulmonary, renal and CNS toxicities; the identification of potentially more efficacious bleomycin analogs is the long-term objective of this proposal. For the four-year period of requested support, we propose to synthesize the bleomycin group antibiotics phleomycin and tallysomycin, which are known to have altered profiles of antitumor activity in animal models. Also proposed for synthesis are bleomycin congeners and """"""""fragments"""""""" that can help to define the structural features in bleomycin responsible for its tumor-seeking properties.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027603-09
Application #
3167727
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1979-09-01
Project End
1989-02-28
Budget Start
1987-03-01
Budget End
1988-02-29
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Virginia
Department
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Hecht, S M (1994) RNA degradation by bleomycin, a naturally occurring bioconjugate. Bioconjug Chem 5:513-26
Kane, S A; Hecht, S M (1994) Polynucleotide recognition and degradation by bleomycin. Prog Nucleic Acid Res Mol Biol 49:313-52
Carter, B J; Murty, V S; Reddy, K S et al. (1990) A role for the metal binding domain in determining the DNA sequence selectivity of Fe-bleomycin. J Biol Chem 265:4193-6
Sebti, S M; DeLeon, J C; Ma, L T et al. (1989) Substrate specificity of bleomycin hydrolase. Biochem Pharmacol 38:141-7
Shipley, J B; Hecht, S M (1988) Bleomycin congeners exhibiting altered DNA cleavage specificity. Chem Res Toxicol 1:25-7
Levy, M J; Hecht, S M (1988) Copper(II) facilitates bleomycin-mediated unwinding of plasmid DNA. Biochemistry 27:2647-50
Ehrenfeld, G M; Shipley, J B; Heimbrook, D C et al. (1987) Copper-dependent cleavage of DNA by bleomycin. Biochemistry 26:931-42
Hecht, S M (1986) DNA strand scission by activated bleomycin group antibiotics. Fed Proc 45:2784-91
Ehrenfeld, G M; Rodriguez, L O; Hecht, S M et al. (1985) Copper(I)-bleomycin: structurally unique complex that mediates oxidative DNA strand scission. Biochemistry 24:81-92
Sugiyama, H; Ehrenfeld, G M; Shipley, J B et al. (1985) DNA strand scission by bleomycin group antibiotics. J Nat Prod 48:869-77