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

Abstract

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.

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    MeSH

    Animals
    Bromodeoxyuridine
    Cell Line
    Cell Survival
    DNA
    DNA Damage
    DNA Repair
    Dose-Response Relationship, Radiation
    Idoxuridine
    Radiation-Sensitizing Agents
    Thymidine

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    3570896

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Enhancement of X ray induced DNA damage by pre-treatment with halogenated pyrimidine analogs. AU - Kinsella,T J, AU - Dobson,P P, AU - Mitchell,J B, AU - Fornace,A J,Jr PY - 1987/5/1/pubmed PY - 2001/3/28/medline PY - 1987/5/1/entrez SP - 733 EP - 9 JF - International journal of radiation oncology, biology, physics JO - Int. J. Radiat. Oncol. Biol. Phys. VL - 13 IS - 5 N2 - 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. SN - 0360-3016 UR - https://www.unboundmedicine.com/medline/citation/3570896/Enhancement_of_X_ray_induced_DNA_damage_by_pre_treatment_with_halogenated_pyrimidine_analogs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0360-3016(87)90292-6 DB - PRIME DP - Unbound Medicine ER -