Enhancement of X ray induced DNA damage by pre-treatment with halogenated pyrimidine analogs

Journal Article · Fri May 01 00:00:00 EDT 1987 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(87)90292-6· OSTI ID:6467397

Kinsella, T J; Dobson, P P; Mitchell, J B; Fornace, Jr, A J

The use of the halogenated pyrimidine analogs, including bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd), as potential clinical radiosensitizers is an area of renewed clinical research. Cellular radiation effects of these analogs using clinically achievable steady state plasma levels (10(-7)-10(-5) M) were measured in vitro using exponentially growing Chinese hamster V79 cells. Radiation response was determined by clonogenic survival and by the production of DNA single strand (SSB) and double strand breaks (DSB) using filter elution techniques. Replacement of thymidine in DNA by BrdUrd or IdUrd was also determined. Drug exposure of BrdUrd or IdUrd for two population doublings (17 hr) prior to irradiation resulted in a progressive reduction of n and D0 compared to untreated controls over the drug dose range of 10(-7)-10(-5) M. The percent thymidine replacement increased from 1% at 10(-7) M to 5% at 10(-6) M to 23% at 10(-5) M. Using a 17 hr exposure at 10(-5) of BrdUrd or IdUrd, the production of SSB and DSB was increased by greater than or equal to 2X and greater than or equal to 1.5X respectively. No differences in the kinetics of repair of SSB and DSB were found following 3 hr of post-irradiation repair. We conclude that in this in vitro model, there appears to be a direct relationship between percent thymidine replacement, reduction of radiation survival parameters (n, D0), and the production of DNA strand breaks in the clinically achievable dose range of these halogenated pyrimidine analogs. These filter elution assays may be adapted to in vivo studies and possibly may allow for monitoring of radiation-induced DNA damage and repair in clinical tumor specimens treated with these radiosensitizers.

• Research Organization: National Cancer Institute, Bethesda, MD
• OSTI ID: 6467397
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 5; ISSN IOBPD
• Country of Publication: United States
• Language: English

Related Subjects

560120* -- Radiation Effects on Biochemicals
Cells
& Tissue Culture
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
ANTIMETABOLITES
AZINES
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
BROMOURACILS
BUDR
CELL KILLING
DEOXYURIDINE
DNA
DNA REPAIR
DRUGS
HALOGEN COMPOUNDS
HAMSTERS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
IODINE COMPOUNDS
MAMMALS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC BROMINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIMIDINES
RADIOINDUCTION
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
RECOVERY
REPAIR
RIBOSIDES
RODENTS
STRAND BREAKS
THYMIDINE
URACILS
VERTEBRATES