Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors

Results of a Phase I Study

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

Research output: Contribution to journalArticle

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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, apotent topoisomerase II inhibitor, inhypoxic 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, and1cervix) received a single 200 mg/m2 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 μg/g) and head and neck (mean 0.65 μg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations ≥0.2 μg/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 lowconcentrations of AQ4 (mean 0.037 Ag/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 AQ4Nas a novel tumor-targeting agent in future clinical studies.

Original languageEnglish
Pages (from-to)1096-1104
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number4
DOIs
Publication statusPublished - 15 Feb 2008
Externally publishedYes

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Prodrugs
Neoplasms
Glioblastoma
AQ4N
Hypoxia
Neck
Head
Topoisomerase II Inhibitors
Facilitative Glucose Transport Proteins
Tandem Mass Spectrometry
Confocal Microscopy
Liquid Chromatography
Reference Values
Urinary Bladder
Breast
Research Design
Animal Models
Fluorescence

Cite this

Albertella, Mark R. ; Loadman, Paul M. ; Jones, Philip H. ; Phillips, Roger M. ; Rampling, Roy ; Burnet, Neil ; Alcock, Chris ; Anthoney, Alan ; Vjaters, Egils ; Dunk, Chris R. ; Harris, Peter A. ; Wong, Alvin ; Lalani, Alshad S. ; Twelves, Chris J. / Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors : Results of a Phase I Study. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 4. pp. 1096-1104.
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title = "Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors: Results of a Phase I Study",
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, apotent topoisomerase II inhibitor, inhypoxic 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, and1cervix) received a single 200 mg/m2 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 μg/g) and head and neck (mean 0.65 μg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations ≥0.2 μg/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 lowconcentrations of AQ4 (mean 0.037 Ag/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 AQ4Nas a novel tumor-targeting agent in future clinical studies.",
author = "Albertella, {Mark R.} and Loadman, {Paul M.} and Jones, {Philip H.} and Phillips, {Roger M.} and Roy Rampling and Neil Burnet and Chris Alcock and Alan Anthoney and Egils Vjaters and Dunk, {Chris R.} and Harris, {Peter A.} and Alvin Wong and Lalani, {Alshad S.} and Twelves, {Chris J.}",
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Albertella, MR, Loadman, PM, Jones, PH, Phillips, RM, Rampling, R, Burnet, N, Alcock, C, Anthoney, A, Vjaters, E, Dunk, CR, Harris, PA, Wong, A, Lalani, AS & Twelves, CJ 2008, 'Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors: Results of a Phase I Study', Clinical Cancer Research, vol. 14, no. 4, pp. 1096-1104. https://doi.org/10.1158/1078-0432.CCR-07-4020

Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors : Results of a Phase I Study. / Albertella, Mark R.; Loadman, Paul M.; Jones, Philip H.; Phillips, Roger M.; Rampling, Roy; Burnet, Neil; Alcock, Chris; Anthoney, Alan; Vjaters, Egils; Dunk, Chris R.; Harris, Peter A.; Wong, Alvin; Lalani, Alshad S.; Twelves, Chris J.

In: Clinical Cancer Research, Vol. 14, No. 4, 15.02.2008, p. 1096-1104.

Research output: Contribution to journalArticle

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T1 - Hypoxia-Selective Targeting by the Bioreductive Prodrug AQ4N in Patients with Solid Tumors

T2 - Results of a Phase I Study

AU - Albertella, Mark R.

AU - Loadman, Paul M.

AU - Jones, Philip H.

AU - Phillips, Roger M.

AU - Rampling, Roy

AU - Burnet, Neil

AU - Alcock, Chris

AU - Anthoney, Alan

AU - Vjaters, Egils

AU - Dunk, Chris R.

AU - Harris, Peter A.

AU - Wong, Alvin

AU - Lalani, Alshad S.

AU - Twelves, Chris J.

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Y1 - 2008/2/15

N2 - 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, apotent topoisomerase II inhibitor, inhypoxic 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, and1cervix) received a single 200 mg/m2 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 μg/g) and head and neck (mean 0.65 μg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations ≥0.2 μg/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 lowconcentrations of AQ4 (mean 0.037 Ag/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 AQ4Nas a novel tumor-targeting agent in future clinical studies.

AB - 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, apotent topoisomerase II inhibitor, inhypoxic 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, and1cervix) received a single 200 mg/m2 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 μg/g) and head and neck (mean 0.65 μg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations ≥0.2 μg/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 lowconcentrations of AQ4 (mean 0.037 Ag/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 AQ4Nas a novel tumor-targeting agent in future clinical studies.

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