Abstract

This project will examine the relationship between the effects of strand scission antitumor agents on DNA structure and cytotoxicity/therapeutic effectiveness. There are 4 main aims. (i) Develop a model system designed to select combinations of DNA reactive drugs in which the therapeutic potential of a strand scission drug is enhanced. The drug's cellular target, nucleosomal DNA, will be perturbed by a second antitumor drug that can unwind DNA structure. The change in scission drug action on nucleosomal DNA, including rate of endonucleolytic digestion and site of action will be determined along with changes in drug cytotoxicity. (ii) Analyze additional DNA strand scission drugs for their effects on nucleosomal DNA. New strand scission drugs will be tested to determine their ability to interact with nucleosomal DNA. This will extend the range of drugs that can be tested in the drug combinations described in aim 1. (iii) Analyze the effects of DNA strand scission drugs on nucleosomal DNA in vivo. These studies will extend our in vitro observations to show that these agents behave in a similar fashion in vivo. The combination drug analysis will culminate in relating drug action on nucleosomal DNA to changes in therapeutic effectiveness. (iv) Analyze DNA strand scission drug interaction with actively transcribing genes and replicating chromatin. This work will extend scission drug effects on nucleosoma DNA to how these agents cleave transcribing genes and replicating chromatin. DNA perturbing drugs will be used to modify scission drug action on the unique regions of nucleosomal DNA. Changes in drug action will be correlated with changes in cytotoxicity in vitro and therapeutic effectiveness in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028495-05
Application #
3168177
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1980-07-01
Project End
1987-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
5
Fiscal Year
1985
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
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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