EFFECTS OF THE METHOXYMORPHOLINO DERIVATIVE OF DOXORUBICIN AND ITS BIOACTIVATED FORM VERSUS DOXORUBICIN ON HUMAN LEUKEMIA AND LYMPHOMA CELL-LINES AND NORMAL BONE-MARROW

The methoxymorpholino derivative of doxorubicin (MMDX; FCE 23672) has recently entered clinical trials because of its broad spectrum of preclinical antitumor activity and non-cross-resistance in multidrug-resistant (MDR) tumor models. MMDX is activated in the liver to a >10 times more potent metabolite that cross-links DNA. To assess the potential of this drug in hematologic malignancies, we studied the myelotoxicity in vitro and antitumor effect of MMDX as well as its bioactivated form (MMDX+) in a panel of 14 different human leukemia and lymphoma cell lines. The tumor specificity of MMDX in CEM and K562 cells was similar to that of doxorubicin (DOX), and that of MMDX+ was slightly superior. All of the 14 cell lines were found to be more sensitive to MMDX and MMDX+ than were granulocyte-macrophage progenitors. On a molar basis, MMDX was approximately 3 - 100 times more active than DOX, and MMDX+ was 10-1,000 times more potent than DOX. The cytotoxic effect of MMDX and MMDX+ in two P-glycoprotein-positive MDR sublines was greatly improved in comparison with that of DOX. Whereas the response to DOX in the different leukemia and lymphoma cell lines was highly heterogeneous, the response to MMDX and MMDX+ was rather homogeneous. The novel anthracycline MMDX and its bioactivated form MMDX+ are highly active against this panel of human leukemia and lymphoma cell lines and demonstrate potentially greater selectivity for tumor cells in vitro as compared with normal bone marrow precursors.