Hematotoxicity on human bone marrow- and umbilical cord blood-derived progenitor cells and in vitro therapeutic index of methoxymorpholinyldoxorubicin and its metabolites

Michele Ghielmini, Emilia Colli, Giovanna Bosshard, Giulia Pennella, Cristina Geroni, Valter Torri, Maurizio D'Incalci, Franco Cavalli, Cristiana Sessa

Research output: Contribution to journalArticle

Abstract

Purpose: MMDX {3'-deamino-3'-[2(S)-methoxy-4-morpholinyl] doxorubicin}, an anthracycline derivative active in vitro and in vivo against multdrug-resistant tumors, is currently under investigation in phase I clinical trials. In vivo it is metabolically activated, resulting in more cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivated MMDX on hematopoietic progenitors and tumor cell lines. Methods: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-derived clonogenic cells, whereas the metabolites were tested on hCB only. All substances were tested on seven tumor cell lines. Results: BM cells proved to be twice as sensitive as hCB cells to cytotoxics, and MMDX was twice as toxic as DX against hCB cells; MMDX activated with normal rat-liver microsomes and with dexamethasone-induced rat microsomes were, respectively, 70 and 230 times more toxic than MMDX. A comparison of the cytotoxic concentrations on hematopoietic progenitors and tumor cells, revealed that DX and MMDX had 5- fold stronger activity on tumor cell lines than on granulocyte/macrophage colony-forming cells (GM-CFCs), whereas bioactivated MMDX showed comparable cytotoxicity against tumor cells and hematopoietic progenitors. Conclusions: MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.

Original languageEnglish
Pages (from-to)235-240
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume42
Issue number3
DOIs
Publication statusPublished - 1998

Keywords

  • Anthracyclines
  • Clonogenic tests
  • Morpholinyldoxorubicin
  • Toxicology

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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