The new
anthracycline analogue 3'-deamino-3'-(3-cyano-4-morpholinyl)
doxorubicin (
MRA-CN) is an intensely potent compound that has been shown to be 100-1,000 times more potent than
doxorubicin (DOX) in vivo and in vitro. In addition,
MRA-CN has been non-cross-resistant with DOX in DOX-selected models of multidrug resistance. We now report the effect of
MRA-CN (and DOX) on
leukemia cell lines established from patients with common, T-cell, and B-cell
acute lymphoblastic leukemia, as well as with monoblastic
leukemia. The effect of
MRA-CN on the
leukemia cells was compared to its toxicity on normal myeloid progenitors (therapeutic ratio) and to the effect of DOX on the
leukemia and normal cells.
MRA-CN was found to be 100 times more potent than DOX against normal myeloid progenitors--colony-forming units, granulocyte-macrophage (CFU-GM)--and 40-240 times more potent than DOX against
leukemia cell lines. In addition, the therapeutic ratio was uniformly greater than 1, indicating that each
leukemia cell line tested was more sensitive than CFU-GM to
MRA-CN in vitro. There was a lack of correlation between
MRA-CN and DOX at a
drug concentration at which the colony formation is inhibited by 50% in the
leukemia cell lines (correlation coefficient = 0.38), which supported the previous reports of non-cross-resistance between these two agents. The favorable therapeutic ratio, the non-cross-resistance with DOX, and the previously described lack of
cardiac toxicity all make
MRA-CN an attractive candidate for clinical trials in patients with acute
leukemia.