The long-term objective is to elucidate at the molecular level the basis of therapeutic efficacy of DNA strand scission agents when used alone or in combination. Initially, we would like to clarify whether these type of drugs are cytotoxic because of 1) an accumulation of random damage to the genome or 2) damage to specific regions of the genome. The identification of novel and/or specific sites of drug action will be assessed for their relationship to drug-induced cytotoxicity.
The specific aims are: 1. Evaluate the influence of increasing complexity of the DNA environment and the ability of drugs to cleave DNA. Insights about how the structure and environment of DNA influence the DNA damaging potential and its repair of drugs or drug combinations are to be sought. The assays provide quantitative data on a strand scissions drug's ability to induce single and/or double stranded cleavages into DNA in increasingly complex environments (cell-free DNA to mouse studies). 2. Determine preferential sites of drug action on genomic DNA. This project will evaluate preferential interaction of DNA strand scission agents within genomic DNA. The objective is to search for indications that drugs selectively attack genomic DNA, that is whether there is site specific DNA damage. In addition, preferential damage and repair of various subpopulations of genomic DNA (transcribing and replicating chromatin) is evaluated. 3. Assess the possible relationships between cytotoxic potential and drug damage to genomic DNA. Three specific studies are proposed: Study 1. Identification of drugs which possess unique abilities to interact with genomic DNA. Study 2. Ascertain which types of drug interactions with genomic DNA can predict cytotoxic capability. Study 3. Evaluate drug combinations designed to modulate specific drug effects on the genome with a corresponding change in cytotoxicity. Finally, drugs alone or in combinations are to be evaluated for improved therapeutic benefit in tumor-bearing mice by monitoring drug action on a neoplastically transforming episomal element.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028495-09
Application #
3168180
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1980-07-01
Project End
1991-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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
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
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

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