Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243)

Cristiana Sessa, Massimo Zucchetti, Michele Ghielmini, Jean Bauer, Maurizio D'Incalci, Jolanda De Jong, Huguette Naegele, Simona Rossi, Maria Adele Pacciarini, Letizia Domenigoni, Franco Cavalli

Research output: Contribution to journalArticlepeer-review


Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non- cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m2. Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 μg/m2. The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m2, with neutropenia grade 3-4 in two of three patients: Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m2, with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a

Original languageEnglish
Pages (from-to)403-410
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Issue number5
Publication statusPublished - 1999


  • Anthracycline analogs
  • Hematotoxicology
  • Methoxymorpholinyl doxorubicin
  • Oral chemotherapy
  • Phase I

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology


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