Abstract

The intent of the proposed study is to: a) determine the radiochemical mechanisms involved in the efficient radiation potentiation of S. typhimurium cell killing observed with Rh(III) monomeric complexes; b) determine the effectiveness of Rh(III) complex-induced radiation potentiation as it relates to the concentration of the Rh complexes present at time of irradiation of S. typhimurium cells; c) determine the variable extent of radiation potentiation that the Rh(III) complexes cause among irradiated bacterial strains differering in DNA repair capacity. Radiation potentiation of cell killing by Rh(III) complexes is reported for the first time. The Rh complexes are essentially nontoxic, yet achieve a degree of hypoxic cell radiation potentiation that is unequalled in the literature on metal complexes to date. The intended characterization described above will elucidate a diverse blend of radiochemical mechanisms that in some cases in part include toxic product activity and in other cases not, that include at times only reductive pathways of action and at times both oxidative and reductive pathways, that involve a diverse response to scavenging of the hydroxyl radical and the hydrated electron, and that are variably sensitive to DNA repair systems of the irradiated biological test system. The understanding of the mechanisms by which metal complexes serve as radiation sensitizers and potentiators of cell killing will be advanced by this proposed study. The potential exists for eventual use of one or more of these Rh complexes in combination with radiation therapy. Indeed, this potential is now developing with one of the Rh(III) complexes described. The steady state radiochemical mechanisms of Rh complex action will be studied by irradiating suspensions of S. typhimurium cells in: a) the presence compared to the absence of Rh complexes selected as much as possible for systematic relationships, b) hydroxyl radical scavenger; c) hydrated electron scavenger; d) catalase. DNA damage will be investigated. Rh uptake by cells will be determined by atomic absorption spectroscopy. The kinetic radiochemical mechanism of action of these Rh complexes will be studied by pulse radiolysis techniques. The bacterial systems to be used are S. typhimurium TM35 (lacks excision repair, lacks SOS repair function), S. typhimurium TM677 (excision repair deficient, contains plasmid pKM101 with the SOS repair function), and S. typhimurium TA1978 (excision repair proficient, lacks SOS repair function).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041571-02
Application #
3182213
Study Section
Radiation Study Section (RAD)
Project Start
1986-09-01
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755