Abstract | PURPOSE:
AQ4N is a novel bioreductive prodrug under clinical investigation. Preclinical evidence shows that AQ4N penetrates deeply within tumors and undergoes selective activation to form AQ4, a potent topoisomerase II inhibitor, in hypoxic regions of solid tumors. This proof-of-principle, phase I study evaluated the activation, hypoxic selectivity, and safety of AQ4N in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Thirty-two patients with cancer (8 glioblastoma, 9 bladder, 8 head and neck, 6 breast, and 1 cervix) received a single 200 mg/m(2) dose of AQ4N before elective surgery. AQ4 and AQ4N levels in 95 tissues ( tumor, healthy tissue) were assessed by liquid chromatography-tandem mass spectrometry. Tissue sections were also analyzed for AQ4 fluorescence using confocal microscopy, and for expression of the hypoxia-regulated glucose transporter, Glut-1. RESULTS: Activated AQ4 was detected in all tumor samples with highest levels present in glioblastoma (mean 1.2 microg/g) and head and neck (mean 0.65 microg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations > or = 0.2 microg/g, levels previously shown to be active in preclinical studies. In 24 of 30 tumor samples, AQ4 was detected at higher concentrations than in adjacent normal tissue ( tumor to normal ratio range 1.1-63.6); distant skin samples contained very low concentrations of AQ4 (mean 0.037 microg/g). Microscopic evaluation of tumor sections revealed that AQ4 colocalized within regions of Glut-1+ hypoxic cells. CONCLUSIONS:
AQ4N was activated selectively in hypoxic regions in human solid tumors. Intratumoral concentrations of AQ4 exceeded those required for activity in animal models and support the evaluation of AQ4N as a novel tumor-targeting agent in future clinical studies.
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Authors | Mark R Albertella, Paul M Loadman, Philip H Jones, Roger M Phillips, Roy Rampling, Neil Burnet, Chris Alcock, Alan Anthoney, Egils Vjaters, Chris R Dunk, Peter A Harris, Alvin Wong, Alshad S Lalani, Chris J Twelves |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 14
Issue 4
Pg. 1096-104
(Feb 15 2008)
ISSN: 1078-0432 [Print] United States |
PMID | 18281542
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anthraquinones
- Antineoplastic Agents
- Excitatory Amino Acid Transporter 2
- Prodrugs
- AQ4N
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Topics |
- Anthraquinones
(metabolism, pharmacokinetics, therapeutic use)
- Antineoplastic Agents
(metabolism, pharmacokinetics, therapeutic use)
- Cell Hypoxia
- Excitatory Amino Acid Transporter 2
(biosynthesis, drug effects)
- Humans
- Immunohistochemistry
- Microscopy, Confocal
- Neoplasms
(drug therapy)
- Prodrugs
(metabolism, pharmacokinetics, therapeutic use)
- Tissue Distribution
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