AQ4N is a novel prodrug that is selectively bioreduced to AQ4, a topoisomerase II inhibitor, in hypoxic tumor. This study assessed the maximum tolerated dose and pharmacokinetics of AQ4N when administered weekly in patients with advanced cancers. AQ4N was administered as a 30-minute i.v. infusion on days 1, 8, and 15 of a 28-day cycle in eight dose cohorts ranging from 12 to 1,200 mg/m(2). Accelerated titration design was used and the maximum tolerated dose was defined as the highest dose at which fewer than two of six patients had a dose-limiting toxicity. Sixteen patients were treated with cumulative doses of AQ4N ranging from 61.6 through 9,099.1 mg/m(2). A single patient per cohort was treated up to 384 mg/m(2) without toxicities. At 1,200 mg/m(2), two of five patients experienced a dose-limiting toxicity (grade 5 respiratory failure and grade 3 fatigue). Five cohort assigned patients were treated without toxicity at 768 mg/m(2), establishing this dose as the maximum tolerated dose. Among the most common adverse events observed were fatigue (38%), diarrhea (31%), nausea (25%), vomiting (25%), and anorexia (13%). Anticipated blue coloration of body fluids or skin was observed in all patients. The pharmacokinetics of AQ4N were dose proportional over all doses studied. Three patients experienced stable disease, including a patient with collecting duct renal cancer stable for 25 months. AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m(2). Further combination studies investigating the safety and efficacy of AQ4N are ongoing.