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Pre- and post-irradiation radiosensitization by SR 4233.

E M Zeman1, J M Brown

  • 1Department of Radiation Oncology, Stanford University Medical Center, CA 94305.

International Journal of Radiation Oncology, Biology, Physics
|April 1, 1989
PubMed
Summary

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) selectively kills hypoxic cells by damaging DNA. This bioreductive agent also enhances radiation effects on aerobic cells and inhibits DNA repair.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Radiology

Background:

  • SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent with selective toxicity towards hypoxic cells.
  • Its mechanism involves one-electron reduction under hypoxia, generating a DNA-damaging free radical intermediate.

Purpose of the Study:

  • To investigate the DNA-damaging efficiency of SR 4233 compared to gamma-rays.
  • To explore the radiosensitizing effects of SR 4233 on aerobic cells.
  • To determine SR 4233's impact on the rejoining of radiation-induced DNA double-strand breaks.

Main Methods:

  • Neutral filter elution assay to measure DNA double-strand breaks in Chinese hamster ovary (CHO) cells.
  • Drug and radiation sequencing experiments assessing cell survival and DNA repair.

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  • Hypoxic incubation of aerobic cells with SR 4233 before or after irradiation.

    • Main Results:

    • SR 4233 was more efficient than equitoxic gamma-rays in inducing DNA double-strand breaks in CHO cells.
    • SR 4233 demonstrated radiosensitization of aerobic cells when administered in hypoxic conditions, irrespective of drug dose (2%-30% survival).
    • SR 4233 inhibited the rejoining of radiation-induced DNA double-strand breaks, with inhibition increasing with SR 4233 pretreatment severity.

    Conclusions:

    • SR 4233 possesses potent DNA-damaging capabilities, exceeding gamma-rays under specific conditions.
    • SR 4233 acts as a radiosensitizer for aerobic cells and impairs DNA repair mechanisms.
    • These properties suggest SR 4233's potential as a therapeutic agent in cancer treatment, particularly in combination with radiation therapy.