Phase I and pharmacokinetic studies of DON.
DON, a glutamine antagonist, was administered iv to 26 patients with advanced cancer either once every 3 wks or daily for 3 days every 3 wks to determine toxicity and to look for evidence of therapeutic effect. Total doses ranged from 150 to 600 mg/m2. The single-day schedule produced intolerable nausea and vomiting and no evidence of cytotoxicity at 450-550 mg/m2 given over 10 mins or over 4 hrs. On the 3-day schedule, patients had tolerable gastrointestinal toxic effects at total doses up to 480 mg/m2 given in three equally divided doses by 10-min infusion. This dose also produced cytotoxic activity manifested as transient mild leukopenia and, rarely, thrombocytopenia. No objective responses were seen. Analysis of the plasma elimination of DON demonstrated dose-dependent pharmacokinetic behavior. The parent compound was not detectable in the urine of any patient, indicating extensive metabolism of the drug.
D001391:Azo Compounds / Q000008:administration & dosage*; D003980:Diazooxonorleucine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D014839:Vomiting / Q000139:chemically induced
D001391:Azo Compounds; D003980:Diazooxonorleucine