Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21-28 days. Thirteen patients have received a total of 24 courses (median 2; range 1-3). At the starting dose of 40 mg/m2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m2 DOXeq. Hepatotoxicity was noted in 5/5 patients (1 x WHO grade IV, 1 x WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 x WHO grade IV, 2 x WHO grade III). At 12.5 mg/m2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 micrograms/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83-80.21 micrograms/ml*h with dose-dependent elimination half lives (t1/2 alpha: 0.02-0.87 h; t1/2 beta: 2.69-11.58 h; t1/2 gamma: 41.44-136.58 h).(ABSTRACT TRUNCATED AT 250 WORDS)