Additive and supraadditive interaction between ionizing radiation and pazelliptine, a DNA topoisomerase inhibitor, in Chinese hamster V-79 fibroblasts

Journal Article · Sat Jun 15 00:00:00 EDT 1991 · Cancer Research; (United States)

OSTI ID:5592577

Balosso, J; Giocanti, N; Favaudon, V ^[1]

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1. Unite 219 INSERM, Institut Curie-Biologie, Orsay (France)

The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with gamma-ray irradiation was investigated using Chinese hamster V-79 cells in culture. gamma-ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation----drug sequence with 10% survival as an endpoint. No synergistic potentiation was observed at higher survival or as pazelliptine was applied first. Pazelliptine abolished the low-dose shoulder characteristic of asynchronous cell response to gamma-rays. Although rejoining of radiation-induced DNA strand breaks was completed at the time of drug exposure, pazelliptine brought about a larger amount of DNA strand breaks in preirradiated than in nonirradiated cells. The time and dose dependencies of DNA strand break formation and repair with radiation and/or pazelliptine were analyzed by neutral and alkaline filter elution. Pazelliptine in the micromolar range showed the same pattern of double-stranded cleavable complex formation as expected of a DNA topoisomerase II-targeting agent. At a low concentration of pazelliptine, however, protein-concealed breaks were mostly in the form of single-stranded adducts. Such single-stranded complexes have been reported to occur with some topoisomerase II-targeting drugs; their properties are also reminiscent of those induced by the topoisomerase I poison, camptothecin. It is proposed that topoisomerase poisoning interacts with the repair of radiation-induced lesions.

• OSTI ID: 5592577
• Journal Information: Cancer Research; (United States), Vol. 51:12; ISSN 0008-5472
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ENZYME INHIBITORS
RADIOSENSITIVITY EFFECTS
FIBROBLASTS
GENETIC RADIATION EFFECTS
STRAND BREAKS
RADIOINDUCTION
CLONE CELLS
DNA
DOSE-RESPONSE RELATIONSHIPS
GAMMA RADIATION
HAMSTERS
INDOLES
ISOMERASES
LUNGS
TIME DEPENDENCE
ANIMAL CELLS
ANIMALS
AROMATICS
AZAARENES
AZOLES
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
BODY
CELL CULTURES
CONNECTIVE TISSUE CELLS
ELECTROMAGNETIC RADIATION
ENZYMES
GENETIC EFFECTS
HETEROCYCLIC COMPOUNDS
IONIZING RADIATIONS
MAMMALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRROLES
RADIATION EFFECTS
RADIATIONS
RESPIRATORY SYSTEM
RODENTS
SOMATIC CELLS
VERTEBRATES
560120* - Radiation Effects on Biochemicals
Cells
& Tissue Culture