AQ4N: a new approach to hypoxia-activated cancer chemotherapy
Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. AQ4N is a bioreductive prod...
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| Published in | British journal of cancer Vol. 83; no. 12; pp. 1589 - 1593 |
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| Main Authors | , |
| Format | Journal Article |
| Language | English |
| Published |
Basingstoke
Nature Publishing Group
01.12.2000
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. 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. AQ4N is clearly different in both its mechanism of action and potential bystander effect compared to previously identified bioreductive drugs. In particular AQ4N is the only bioreductive prodrug topoisomerase II inhibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) courses of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they attempt to re-enter the cell cycle. |
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| AbstractList | Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. 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. AQ4N is clearly different in both its mechanism of action and potential bystander effect compared to previously identified bioreductive drugs. In particular AQ4N is the only bioreductive prodrug topoisomerase II inhibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) courses of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they attempt to re-enter the cell cycle. Preclinical studies demonstrate that in vivo AQ4N enhances the anti-tumour effects of radiation and chemotherapeutic agents with a dose-modifying factor of approximately 2.0. With careful scheduling no, or very little, additional normal tissue toxicity should be observed. 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. AQ4N is clearly different in both its mechanism of action and potential bystander effect compared to previously identified bioreductive drugs. In particular AQ4N is the only bioreductive prodrug topoisomerase II inhibitor to enter clinical trials. Targeting this enzyme, which is crucial to cell division, may help sensitize tumours to repeated (fractionated) courses of radiotherapy. This is because in principle, the bioreduction product of AQ4N can inhibit the topoisomerase activity of hypoxic cells as they attempt to re-enter the cell cycle. © 2000 Cancer Research Campaign http://www.bjcancer.com |
| Author | PATTERSON, L. H MCKEOWN, S. R |
| Author_xml | – sequence: 1 givenname: L. H surname: PATTERSON fullname: PATTERSON, L. H organization: Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, Brunswick Square, London WC1N 1AX, United Kingdom – sequence: 2 givenname: S. R surname: MCKEOWN fullname: MCKEOWN, S. R organization: School of Biomedical Sciences, University of Ulster at Jordanstown, Northern Ireland BT37 OQB, United Kingdom |
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| Copyright | 2001 INIST-CNRS Copyright 2000 Cancer Research Campaign. Copyright Nature Publishing Group Dec 2000 Copyright © 2000 Cancer Research Campaign 2000 Cancer Research Campaign |
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| Keywords | Antineoplastic agent DNA topoisomerase (ATP-hydrolysing) Oxygen Anthraquinone derivatives Enzyme Rodentia Enzyme inhibitor Prodrug Malignant tumor Vertebrata Chemotherapy Isomerases Mammalia Treatment Bioreductive drug Mouse Animal Hypoxia |
| Language | English |
| License | CC BY 4.0 Copyright 2000 Cancer Research Campaign. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
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end-page: 1122 article-title: Rat cytochromes P450 (CYP) specifically contribute to the reductive bioactivation of AQ4N, an alkylaminoanthraquinone-di-N-oxide anticancer prodrug publication-title: Xenobiotica contributor: fullname: Patterson, LH – volume: 163 start-page: 50 year: 2000 end-page: 59 article-title: Hypoxia-dependent retinal toxicity of bioreductive anticancer prodrugs in mice publication-title: Toxicol Appl Pharmacol contributor: fullname: Wilson, WR – volume: 6 start-page: 533 year: 1994 end-page: 538 article-title: Aliphatic amine N-oxides of DNA binding agents as bioreductive drugs publication-title: Oncol Res contributor: fullname: Teesdale-Spittle, P – volume: 27 start-page: S43 year: 1996 end-page: 47 article-title: Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N publication-title: Br J Cancer Suppl contributor: fullname: Lee, HH |
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| SubjectTerms | Animals Anthraquinones - therapeutic use Antineoplastic agents Antineoplastic Agents - therapeutic use Biological and medical sciences Cancer research Cancer therapies Cell cycle Cell division Cell Hypoxia Chemotherapy Cytotoxicity Humans Hypoxia Medical research Medical sciences Mini-Review Neoplasms - drug therapy Neoplasms, Experimental - drug therapy Pharmacology. Drug treatments Phosphates Physical properties Prodrugs - therapeutic use Radiation-Protective Agents - therapeutic use Toxicity Tumors |
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