Abstract
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. 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. 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. 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.
Highlights
AQ4N is a novel bioreductive prodrug under clinical investigation
Thirty-three patients from six centers in United Kingdom and Latvia were enrolled between November 2004 and September 2005, of whom 32 received AQ4N and completed the study
At the time of surgery, AQ4N plasma levels were very low (89.8 F 25.0 ng/mL) and represented
Summary
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, 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. Several mechanisms contribute to this, including direct requirement of oxygen for ionizing radiation damage, reduced penetration and delivery of chemotherapeutic agents, and the protective effects of hypoxiaregulated genes These factors, coupled with the increased genetic instability observed in hypoxic cells, facilitate the selection of resistant clones, tumor repopulation, and treatment failure (12 – 14). There is, a strong rationale for the development of novel agents that target treatment-resistant and hypoxic regions of tumors with minimal toxicity to normal tissues. One such agent under clinical investigation is AQ4N (banoxantrone; 1,4-bis {[2-(dimethylamino)ethyl]amino}5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide), a novel prodrug that was designed to be activated to a potent cytotoxin in hypoxic tumor regions (20 – 23). AQ4N has been shown to enhance the therapeutic response to radiation [24, 25], cisplatin [25, 26], and other chemotherapies [25, 27, 28] in preclinical models
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