The objectives of this research project are to study the interaction of nucleic acids with antitumor bifunctional alkylating agents, and to obtain a clearer understanding of the kinetics and mechanisms involved in the crosslinking of nucleic acids at the molecular level. To investigate the kinetics associated with interstrand DNA crosslink formation and the influence of nucleic acid structure on crosslinking processes, a comparative analysis of the dynamics of interstrand crosslinking by the nitrogen mustards and nitrosoureas to native DNAs and polynucleotides of defined sequence will be undertaken using well established spectrophotometric and bioanalytical procedures. Preliminary studies on the interstrand crosslinking of native DNAs by the nitrogen mustard prototype mechlorethamine, HN2, using a spectrofluorimetric crosslink assay method have provided direct measurements of the specific rate constants and activation energy associated with interstrand DNA crosslinking by HN2. Additional studies with synthetic deoxyribopolynucleotide copolymers of defined sequence using an alkaline gel electrophoresis assay in combination with the fluorimetric method have provided direct evidence for base-specific interactions at the HN2 crosslink site. This research proposal describes further work on studies of the interstrand DNA crosslinking processes associated with the nitrogen mustard and nitrosourea class of antitumor drugs. Further characterization of the kinetics and the influence of nucleic acid structure on crosslinking may lead to a better understanding of the mechanisms of action of a wide variety of antitumor DNA alkylating agents, and may ultimately provide a rationale for the interpretation of their diverse biochemical and pharmacological properties at a molecular level.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15CA047734-01
Application #
3437354
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1988-08-01
Project End
1991-07-31
Budget Start
1988-08-01
Budget End
1991-07-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Rochester Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14623