BACKGROUND: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] 
amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a 
prodrug which is selectively activated within hypoxic tissues to AQ4, a 
topoisomerase II inhibitor and DNA intercalator.
PATIENTS AND METHODS: In the phase I study, 22 patients with oesophageal 
carcinoma received an i.v. infusion of AQ4N (22.5-447 mg/m(2)) followed, 2 weeks 
later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte 
AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m(2), biopsies 
of tumour and normal tissue were taken after AQ4N administration.
RESULTS: Drug-related adverse events were blue discolouration of skin and urine, 
grade 2-3 lymphopenia, grade 1-3 fatigue, grade 1-2 anaemia, leucopenia and 
nausea. There were no drug-related serious adverse events (SAEs). Three patients 
had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics 
indicated predictable clearance. Plasma area under the curve (AUC) at 447 
mg/m(2) exceeded AQ4N concentrations in mice at therapeutic doses and tumour 
biopsies contained concentrations of AQ4 greater than those in normal tissue. 
Tumour concentrations of AQ4 exceeded in vitro IC(50) values for most cell lines 
investigated.
CONCLUSIONS: No dose-limiting toxic effects were observed and a maximum 
tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 
447 mg/m(2) exceeded active levels in preclinical models. This dose was chosen 
for future studies with radiotherapy.