Hematotoxicity on human bone marrow- and umbilical cord blood-derived progenitor cells and in vitro therapeutic index of methoxymorpholinyldoxorubicin and its metabolites.
OBJECTIVE
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.
Ghielmini
M
M
Servizio Oncologico Cantonale, Ospedale S. Giovanni, Bellinzona, Switzerland.
Colli
E
E
Bosshard
G
G
Pennella
G
G
Geroni
C
C
Torri
V
V
D'Incalci
M
M
Cavalli
F
F
Sessa
C
C
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects*; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005312:Fetal Blood / Q000187:drug effects*; D006801:Humans; D013234:Stem Cells / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000903:Antibiotics, Antineoplastic; C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin; C048396:NSC 354646