HEMATOTOXICITY ON HUMAN BONE MARROW-DERIVED AND UMBILICAL-CORD BLOOD-DERIVED PROGENITOR CELLS AND IN-VITRO THERAPEUTIC INDEX OF METHOXYMORPHOLINYLDOXORUBICIN AND ITS METABOLITES

Purpose: MMDX {3'-deamino-3'-[2(S)-methoxy- 4-morpholinyl] doxorubicin }, an anthracycline derivative active in vitro and in vivo against mul tidrug-resistant tumors, is currently under investigation in phase I c linical trials. In vivo it is metabolically activated, resulting in mo re cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivat ed MMDX on hematopoietic progenitors and tumor cell lines. Methods: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-d erived clonogenic cells, whereas the metabolites were tested on hCB on ly. 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 n ormal rat-liver microsomes and with dexamethasone-induced rat microsom es were, respectively, 70 and 230 times more toxic than MMDX. A compar ison 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 ag ainst tumor cells and hematopoietic progenitors. Conclusions: MMDX met abolites are very potent but display a lower degree of tumor selectivi ty than MMDX. Strategies to reduce MMDX metabolization should be devel oped to optimize the therapeutic index of this new anthracycline.