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

@article{Patterson2000EnhancementOC,
  title={Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent},
  author={L. H. Patterson and S. McKeown and K. Ruparelia and J. Double and M. Bibby and S. Cole and I. Stratford},
  journal={British Journal of Cancer},
  year={2000},
  volume={82},
  pages={1984 - 1990}
}
AQ4 (1,4-Bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxyanthracene-9, 10-dione) is a prodrug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase II 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… Expand
AQ4N: a new approach to hypoxia-activated cancer chemotherapy
TLDR
AQ4N is a bioreductive prodrug of a potent, stable, reduction product which binds non-covalently to DNA, facilitating antitumour activity in both hypoxic and proximate oxic tumour cells. Expand
In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts
TLDR
This is the first demonstration that AQ4N will increase the efficacy of chemoradiotherapy in preclinical models; the intratumoral levels of AQ4 found in this study are comparable with tumor AQ4 levels found in a recent phase I clinical study, which suggests that these levels could be potentially therapeutic. Expand
BIOREDUCTIVELY ACTIVATED ANTITUMOR N-OXIDES: THE CASE OF AQ4N, A UNIQUE APPROACH TO HYPOXIA-ACTIVATED CANCER CHEMOTHERAPY
TLDR
Although AQ4N has little or no intrinsic cytotoxic activity per se it enhances the antitumor effects of radiation and conventional chemotherapeutic agents, is pharmacokinetically stable, and is a substrate for cytochrome P450 (CYP). Expand
Bioreductive drugs: from concept to clinic.
TLDR
This paper reviews the pre-clinical data and discusses the clinical studies that have been reported on the development of bioreductive drugs that are specifically designed to target hypoxic tumour cells. Expand
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs
  • R. Phillips
  • Biology, Medicine
  • Cancer Chemotherapy and Pharmacology
  • 2015
TLDR
Current progress in the development of hypoxia-activated prodrugs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples are described. Expand
Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors: Results of a Phase I Study
TLDR
Intratumoral concentrations of AQ4 exceeded those required for activity in animal models and support the evaluation of AQ 4N as a novel tumor-targeting agent in future clinical studies. Expand
The hypoxia-activated ProDrug AQ4N penetrates deeply in tumor tissues and complements the limited distribution of mitoxantrone.
TLDR
Clinical evaluation of AQ4N in combination with conventional anticancer agents, such as mitoxantrone, is supported and results in effective drug exposure over the entire tumor after combined treatment and increases tumor growth delay compared with either drug alone. Expand
The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study.
TLDR
No dose-limiting toxic effects were observed and a maximum tolerated dose was not established, but tumour AQ4 concentrations and plasma AUC at 447 mg/m(2) exceeded active levels in preclinical models. Expand
Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N
TLDR
This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N, which is the only CYP-activated bioreductive agent in clinical trials. Expand
The Japanese experiences with hypoxia-targeting pharmacoradiotherapy: from hypoxic cell sensitisers to radiation-activated prodrugs
TLDR
Tumour hypoxia is a negative factor in cancer radiotherapy and antitumour prodrugs that are activated by irradiation under hypoxic conditions via one-electron reduction have been proposed, which appears promising if the prodrug design can be applied to more potent agents that shall be developed in future. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 57 REFERENCES
Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation.
TLDR
In the model, an increase in the therapeutic index was obtained for radiation treatment when either AQ4N or tirapazamine was administered concurrently, and this was in contrast to mitomycin C which had a marked effect on the radiation induced functional deficit. Expand
DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells.
TLDR
The kinetics of the expression of the DNA damage is consistent with this hypothesis and shows that AQ4 has persistent activity in vivo. Expand
AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo.
TLDR
AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy in mice bearing the T50/80 mammary carcinoma and was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. Expand
Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia.
TLDR
It is demonstrated that TPZ potentiates tumor cell kill by fractionated radiation in three murine tumors and two human tumor xenografts with no potentiation observed in a third Xenograft, with the results suggesting that the sensitivity of individual tumors to TPZ, although not necessarily the response to TPz plus radiation, might be assessed from measurements of DNA damage using the comet assay. Expand
Tests of two electron-affinic radiosensitizers in vivo using regrowth of an experimental carcinoma.
TLDR
Ro-07-0582 is the most effective sensitizer so far tested, giving an enhancement ratio of up to 2.1 when 1 mg/g is administered intraperitoneally, since no enhancement of well-oxygenated normal tissue has been observed. Expand
Bioreductive drugs and the selective induction of tumour hypoxia.
TLDR
Tumour hypoxia is induced by physically occluding the tumour vascular supply by clamping, or by giving mice 5 mg kg-1 hydralazine, and small enhancements of toxicity are seen withHydralazine in combination with misonidazole in the RIF-1 tumour and mitomycin C in both tumours. Expand
DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides
TLDR
DNA synthesis inhibition and cytotoxicity were greater than expected for AQ6, given its topoisomerase- and DNA-interaction properties, and parallel studies have provided evidence of an additional role for enhanced subcellular accumulation and nuclear targeting. Expand
Tirapazamine: laboratory data relevant to clinical activity.
Tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazine 1,4-dioxide, Tirazone ) is the lead compound in the benzotriazine di-N-oxide class of bioreductive anticancer agents. ExtensiveExpand
Tirapazamine: laboratory data relevant to clinical activity.
TLDR
The preclinical data suggest that it is likely that TPZ will be active in the clinic, particularly when combined with cisplatin, and an analysis based on the area under the curve shows that the doses being used in current Phase II radiotherapy protocols and Phase III chemotherapy protocols should be sufficient to produce clinical activity. Expand
Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512).
TLDR
The unique chemosensitivity of MAC 16 to FAA suggests that this agent has a novel mechanism which may be dependent upon specific biological characteristics of tumours. Expand
...
1
2
3
4
5
...