Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent

LH Patterson, Stephanie McKeown, K Ruparella, JA Double, MC Bibby, S Cole, IJ Stratford

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    Abstract

    AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracen e-9, 10-dione) is a prod rug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase It poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2000 Cancer Research Campaign.
    LanguageEnglish
    Pages1984-1990
    JournalBRITISH JOURNAL OF CANCER
    Volume82
    Issue number12
    Publication statusPublished - Jun 2000

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    Radiotherapy
    Drug Therapy
    Neoplasms
    Radiation
    Poisons
    Combination Drug Therapy
    Pharmaceutical Preparations
    AQ4N
    Intercalating Agents
    Thiotepa
    Hydralazine
    Type I DNA Topoisomerase
    Maximum Tolerated Dose
    Cell Nucleus
    Constriction
    Cyclophosphamide
    Oxides
    Cisplatin
    Appointments and Schedules
    Growth

    Cite this

    Patterson, LH., McKeown, S., Ruparella, K., Double, JA., Bibby, MC., Cole, S., & Stratford, IJ. (2000). Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. BRITISH JOURNAL OF CANCER, 82(12), 1984-1990.
    Patterson, LH ; McKeown, Stephanie ; Ruparella, K ; Double, JA ; Bibby, MC ; Cole, S ; Stratford, IJ. / Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. In: BRITISH JOURNAL OF CANCER. 2000 ; Vol. 82, No. 12. pp. 1984-1990.
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    abstract = "AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracen e-9, 10-dione) is a prod rug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase It poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2000 Cancer Research Campaign.",
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    Patterson, LH, McKeown, S, Ruparella, K, Double, JA, Bibby, MC, Cole, S & Stratford, IJ 2000, 'Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent', BRITISH JOURNAL OF CANCER, vol. 82, no. 12, pp. 1984-1990.

    Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. / Patterson, LH; McKeown, Stephanie; Ruparella, K; Double, JA; Bibby, MC; Cole, S; Stratford, IJ.

    In: BRITISH JOURNAL OF CANCER, Vol. 82, No. 12, 06.2000, p. 1984-1990.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent

    AU - Patterson, LH

    AU - McKeown, Stephanie

    AU - Ruparella, K

    AU - Double, JA

    AU - Bibby, MC

    AU - Cole, S

    AU - Stratford, IJ

    PY - 2000/6

    Y1 - 2000/6

    N2 - AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracen e-9, 10-dione) is a prod rug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase It poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2000 Cancer Research Campaign.

    AB - AQ4 (1,4-Bis-([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracen e-9, 10-dione) is a prod rug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase It poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is same tumour selectivity in the enhanced action of the drugs. (C) 2000 Cancer Research Campaign.

    M3 - Article

    VL - 82

    SP - 1984

    EP - 1990

    JO - BRITISH JOURNAL OF CANCER

    T2 - BRITISH JOURNAL OF CANCER

    JF - BRITISH JOURNAL OF CANCER

    SN - 0007-0920

    IS - 12

    ER -

    Patterson LH, McKeown S, Ruparella K, Double JA, Bibby MC, Cole S et al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. BRITISH JOURNAL OF CANCER. 2000 Jun;82(12):1984-1990.