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

Abstract

PURPOSE:

MMDX [3'-deamino-3'-[2(S)-methoxy-4-morpholinyl] doxorubicin], an anthracycline derivative active in vitro and in vivo against multidrug-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.

• Authors: M Ghielmini, E Colli, G Bosshard, G Pennella, C Geroni, V Torri, M D'Incalci, F Cavalli, C Sessa
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 42 Issue 3 Pg. 235-40 ( 1998) ISSN: 0344-5704 [Print] Germany
• PMID: 9685059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• methoxy-morpholinyl-doxorubicin
• Doxorubicin
• NSC 354646

Topics

• Antibiotics, Antineoplastic (adverse effects, metabolism, pharmacology)
• Bone Marrow (drug effects)
• Doxorubicin (adverse effects, analogs & derivatives, metabolism, pharmacology)
• Fetal Blood (drug effects)
• Humans
• Stem Cells (drug effects)
• Tumor Cells, Cultured (drug effects)
• Tumor Stem Cell Assay