Abstract

A new class of unusually potent antitumor drugs modeled after the alkylating antibiotic CC-1065 (isolated from Streptomyces zelensis) are being developed as clinical candidates. Based upon observations of the parent drug a number of novel features have been noted. The drugs bind within the minor groove of DNA in a highly sequence specific manner. A covalent bond is formed with N3 of adenine under proper steric conditions. While the unusually high cytoxicity activity (at

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028495-12
Application #
3168182
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1980-07-01
Project End
1994-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263

  Publications

McHugh, M M; Woynarowski, J M; Gawron, L S et al. (1995) Effects of the DNA-damaging enediyne C-1027 on intracellular SV40 and genomic DNA in green monkey kidney BSC-1 cells. Biochemistry 34:1805-14
McHugh, M M; Woynarowski, J M; Mitchell, M A et al. (1994) CC-1065 bonding to intracellular and purified SV40 DNA: site specificity and functional effects. Biochemistry 33:9158-68
Zsido, T J; Beerman, T A; Meegan, R L et al. (1992) Resistance of CHO cells expressing P-glycoprotein to cyclopropylpyrroloindole (CPI) alkylating agents. Biochem Pharmacol 43:1817-22
Zsido, T J; Woynarowski, J M; Baker, R M et al. (1991) Induction of heat-labile sites in DNA of mammalian cells by the antitumor alkylating drug CC-1065. Biochemistry 30:3733-8
Cullinan, E B; Gawron, L S; Rustum, Y M et al. (1991) Extrachromosomal chromatin: novel target for bleomycin cleavage in cells and solid tumors. Biochemistry 30:3055-61
Vertino, P M; Beerman, T A; Kelly, E J et al. (1991) Selective cellular depletion of mitochondrial DNA by the polyamine analog N1,N12-bis(ethyl)spermine and its relationship to polyamine structure and function. Mol Pharmacol 39:487-94
Rauscher 3rd, F J; Beerman, T A; Baker, R M (1990) Characterization of auromomycin-resistant hamster cell mutants that display a multidrug resistance phenotype. Mol Pharmacol 38:198-206
Woynarowski, J M; Beerman, T A (1989) Preferential effect of bleomycin on newly replicated chromatin in nuclei from L1210 cells. Biochim Biophys Acta 1007:116-9
Beckmann, R P; Beerman, T A (1989) Use of an inducible hybrid viral gene as a model for evaluating drug effects on gene expression. Mol Pharmacol 35:433-42
Van Roey, P; Beerman, T A (1989) Crystal structure analysis of auromomycin apoprotein (macromomycin) shows importance of protein side chains to chromophore binding selectivity. Proc Natl Acad Sci U S A 86:6587-91

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