title: Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules.
abstract: OBJECTIVE
  To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple-dosing schedules.
  
  
  METHODS
  PZA was administered on a single-dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively.
  
  
  RESULTS
  On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity.
  
  
  CONCLUSIONS
  Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single- and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.
authors.affiliation: Johns Hopkins Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: D A
authors.initials: DA
authors.lastname: Noe
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: S E
authors.initials: SE
authors.lastname: Sartorious
authors.forename: M K
authors.initials: MK
authors.lastname: Bowling
authors.forename: T L
authors.initials: TL
authors.lastname: Chen
authors.forename: B G
authors.initials: BG
authors.lastname: Lubejko
authors.forename: S H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
mesh_terms: D000166:Acridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004273:DNA, Neoplasm / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007364:Intercalating Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012074:Remission Induction; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D011720:Pyrazoles; C064541:NSC 366140