Doxorubicin and the alkylating anthracycline 3'-deamino-3'-(3-cyano-4-morpholinyl) doxorubicin: comparative in vitro potency against leukemia and bone marrow cells.
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.
Beckman
R A
RA
Department of Pediatrics, Stanford University School of Medicine, CA 94305.
McFall
P J
PJ
Sikic
B I
BI
Smith
S D
SD
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D004351:Drug Resistance; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin