Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo

SR McKeown, MV HEJMADI, IA MCINTYRE, JJA MCALEER, LH PATTERSON

    Research output: Contribution to journalArticle

    66 Citations (Scopus)

    Abstract

    AQ4N (1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxy- anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reduction, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of AQ4N was investigated in B6D2F(1) mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in combination with hypobaric hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by weight loss post treatment. This was low for AQ4N and was less than that obtained with the bioreductive drugs, RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of AQ4N was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When AQ4N (200 mg kg(-1)) was combined with single dose radiation (12 Gy) the drug was shown to have an additive interaction with radiation. This was obtained even if the drug was administered from 4 days before to 6 h after radiation treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg(-1)) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.
    LanguageEnglish
    Pages76-81
    JournalBRITISH JOURNAL OF CANCER
    Volume72
    Issue number1
    Publication statusPublished - Jul 1995

    Fingerprint

    Oxides
    tirapazamine
    Radiation
    Pharmaceutical Preparations
    Neoplasms
    Radiation Dosage
    AQ4N
    Drug Combinations
    Weight Loss
    Appointments and Schedules
    Radiotherapy
    Breast Neoplasms
    DNA
    Therapeutics

    Keywords

    • BIOREDUCTIVE DRUGS
    • RADIATION
    • TUMOR HYPOXIA

    Cite this

    McKeown, SR., HEJMADI, MV., MCINTYRE, IA., MCALEER, JJA., & PATTERSON, LH. (1995). Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo. BRITISH JOURNAL OF CANCER, 72(1), 76-81.
    McKeown, SR ; HEJMADI, MV ; MCINTYRE, IA ; MCALEER, JJA ; PATTERSON, LH. / Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo. In: BRITISH JOURNAL OF CANCER. 1995 ; Vol. 72, No. 1. pp. 76-81.
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    abstract = "AQ4N (1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxy- anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reduction, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of AQ4N was investigated in B6D2F(1) mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in combination with hypobaric hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by weight loss post treatment. This was low for AQ4N and was less than that obtained with the bioreductive drugs, RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of AQ4N was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When AQ4N (200 mg kg(-1)) was combined with single dose radiation (12 Gy) the drug was shown to have an additive interaction with radiation. This was obtained even if the drug was administered from 4 days before to 6 h after radiation treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg(-1)) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.",
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    author = "SR McKeown and MV HEJMADI and IA MCINTYRE and JJA MCALEER and LH PATTERSON",
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    McKeown, SR, HEJMADI, MV, MCINTYRE, IA, MCALEER, JJA & PATTERSON, LH 1995, 'Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo', BRITISH JOURNAL OF CANCER, vol. 72, no. 1, pp. 76-81.

    Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo. / McKeown, SR; HEJMADI, MV; MCINTYRE, IA; MCALEER, JJA; PATTERSON, LH.

    In: BRITISH JOURNAL OF CANCER, Vol. 72, No. 1, 07.1995, p. 76-81.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Aq4n - an alkylaminoanthraquinone n-oxide showing bioreductive potential and positive interaction with radiation in-vivo

    AU - McKeown, SR

    AU - HEJMADI, MV

    AU - MCINTYRE, IA

    AU - MCALEER, JJA

    AU - PATTERSON, LH

    PY - 1995/7

    Y1 - 1995/7

    N2 - AQ4N (1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxy- anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reduction, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of AQ4N was investigated in B6D2F(1) mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in combination with hypobaric hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by weight loss post treatment. This was low for AQ4N and was less than that obtained with the bioreductive drugs, RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of AQ4N was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When AQ4N (200 mg kg(-1)) was combined with single dose radiation (12 Gy) the drug was shown to have an additive interaction with radiation. This was obtained even if the drug was administered from 4 days before to 6 h after radiation treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg(-1)) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.

    AB - AQ4N (1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxy- anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reduction, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of AQ4N was investigated in B6D2F(1) mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in combination with hypobaric hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by weight loss post treatment. This was low for AQ4N and was less than that obtained with the bioreductive drugs, RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of AQ4N was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When AQ4N (200 mg kg(-1)) was combined with single dose radiation (12 Gy) the drug was shown to have an additive interaction with radiation. This was obtained even if the drug was administered from 4 days before to 6 h after radiation treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg(-1)) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.

    KW - BIOREDUCTIVE DRUGS

    KW - RADIATION

    KW - TUMOR HYPOXIA

    M3 - Article

    VL - 72

    SP - 76

    EP - 81

    JO - BRITISH JOURNAL OF CANCER

    T2 - BRITISH JOURNAL OF CANCER

    JF - BRITISH JOURNAL OF CANCER

    SN - 0007-0920

    IS - 1

    ER -