Hypobaric hypoxia - a method for testing bioreductive drugs invivo

JJA MCALEER, SR McKeown, MP MACMANUS, TRJ LAPPIN, JM BRIDGES

    Research output: Contribution to journalArticle

    Abstract

    Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide). BDF mice bearing the T50/80 mammary carcinoma were treated with these agents over a range of doses under normobaric (oxic) and hypobaric (hypoxic) conditions. The time taken for the tumor to double treatment volume (volume doubling time) was used as a measure of anti-tumor effect. Volume doubling time was plotted against log dose and dose response curves were fitted. A dose enhancement ratio (the ratio of drug doses required to give an equivalent anti-tumor effect under oxic and hypoxic conditions) was determined. The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia. For Nitromin, no significant dose response effect was obtained under oxic conditions precluding the calculation of the dose enhancement ratio. SR 4233 was found to have increased systemic toxicity when combined with hypobaric hypoxia, suggesting that it is more readily activated than the other drugs tested. This in vivo test system will allow determination of the dose enhancement ratio for novel bioreductive agents and facilitate their comparison.
    LanguageEnglish
    Pages551-555
    JournalInternational Journal of Radiation Oncology - Biology - Physics
    Volume23
    Issue number3
    DOIs
    Publication statusPublished - 1992

    Fingerprint

    tirapazamine
    hypoxia
    drugs
    Mechlorethamine
    dosage
    Pharmaceutical Preparations
    tumors
    Neoplasms
    augmentation
    Oxides
    Breast Neoplasms
    Hypoxia

    Keywords

    • SR-4233
    • RSU-1069
    • NITROMIN
    • HYPOBARIC HYPOXIA

    Cite this

    MCALEER, JJA., McKeown, SR., MACMANUS, MP., LAPPIN, TRJ., & BRIDGES, JM. (1992). Hypobaric hypoxia - a method for testing bioreductive drugs invivo. 23(3), 551-555. https://doi.org/10.1016/03600(92)90010-F
    MCALEER, JJA ; McKeown, SR ; MACMANUS, MP ; LAPPIN, TRJ ; BRIDGES, JM. / Hypobaric hypoxia - a method for testing bioreductive drugs invivo. 1992 ; Vol. 23, No. 3. pp. 551-555.
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    MCALEER, JJA, McKeown, SR, MACMANUS, MP, LAPPIN, TRJ & BRIDGES, JM 1992, 'Hypobaric hypoxia - a method for testing bioreductive drugs invivo', vol. 23, no. 3, pp. 551-555. https://doi.org/10.1016/03600(92)90010-F

    Hypobaric hypoxia - a method for testing bioreductive drugs invivo. / MCALEER, JJA; McKeown, SR; MACMANUS, MP; LAPPIN, TRJ; BRIDGES, JM.

    Vol. 23, No. 3, 1992, p. 551-555.

    Research output: Contribution to journalArticle

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    AU - MACMANUS, MP

    AU - LAPPIN, TRJ

    AU - BRIDGES, JM

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    N2 - Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide). BDF mice bearing the T50/80 mammary carcinoma were treated with these agents over a range of doses under normobaric (oxic) and hypobaric (hypoxic) conditions. The time taken for the tumor to double treatment volume (volume doubling time) was used as a measure of anti-tumor effect. Volume doubling time was plotted against log dose and dose response curves were fitted. A dose enhancement ratio (the ratio of drug doses required to give an equivalent anti-tumor effect under oxic and hypoxic conditions) was determined. The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia. For Nitromin, no significant dose response effect was obtained under oxic conditions precluding the calculation of the dose enhancement ratio. SR 4233 was found to have increased systemic toxicity when combined with hypobaric hypoxia, suggesting that it is more readily activated than the other drugs tested. This in vivo test system will allow determination of the dose enhancement ratio for novel bioreductive agents and facilitate their comparison.

    AB - Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide). BDF mice bearing the T50/80 mammary carcinoma were treated with these agents over a range of doses under normobaric (oxic) and hypobaric (hypoxic) conditions. The time taken for the tumor to double treatment volume (volume doubling time) was used as a measure of anti-tumor effect. Volume doubling time was plotted against log dose and dose response curves were fitted. A dose enhancement ratio (the ratio of drug doses required to give an equivalent anti-tumor effect under oxic and hypoxic conditions) was determined. The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia. For Nitromin, no significant dose response effect was obtained under oxic conditions precluding the calculation of the dose enhancement ratio. SR 4233 was found to have increased systemic toxicity when combined with hypobaric hypoxia, suggesting that it is more readily activated than the other drugs tested. This in vivo test system will allow determination of the dose enhancement ratio for novel bioreductive agents and facilitate their comparison.

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    MCALEER JJA, McKeown SR, MACMANUS MP, LAPPIN TRJ, BRIDGES JM. Hypobaric hypoxia - a method for testing bioreductive drugs invivo. 1992;23(3):551-555. https://doi.org/10.1016/03600(92)90010-F