title: Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.
abstract: The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
authors.forename: K A
authors.initials: KA
authors.lastname: Havlin
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: J B
authors.initials: JB
authors.lastname: Craig
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: J
authors.initials: J
authors.lastname: Koeller
authors.forename: J N
authors.initials: JN
authors.lastname: Turner
authors.forename: J S
authors.initials: JS
authors.lastname: Luther
authors.forename: G
authors.initials: G
authors.lastname: Clark
authors.forename: K W
authors.initials: KW
authors.lastname: Bair
authors.forename: W
authors.initials: W
authors.lastname: Wargin
mesh_terms: D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D009422:Nervous System Diseases / Q000139:chemically induced; D010689:Phlebitis / Q000139:chemically induced; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D014839:Vomiting / Q000139:chemically induced
chemical_list: D005449:Fluorenes; D007364:Intercalating Agents; D011409:Propylene Glycols; C073380:1,3-propanediol, 2-((3-fluoranthenylmethyl)amino)-2-methyl-