Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.


Journal Article

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.

Full Text

Cited Authors

  • Havlin, KA; Kuhn, JG; Craig, JB; Weiss, GR; Koeller, J; Turner, JN; Luther, JS; Clark, G; Bair, KW; Wargin, W

Published Date

  • August 1991

Published In

Volume / Issue

  • 2 / 4

Start / End Page

  • 357 - 363

PubMed ID

  • 1797191

Pubmed Central ID

  • 1797191

International Standard Serial Number (ISSN)

  • 0959-4973

Digital Object Identifier (DOI)

  • 10.1097/00001813-199108000-00004


  • eng

Conference Location

  • England