Activity of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin in sensitive and resistant L5178Y lymphoblasts in vitro.
An L5178Y murine lymphoblast cell line resistant to 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (MRA-CN), L5178Y/MRA-CN, was isolated and characterized. L5178Y/MRA-CN cells were 9.6-fold resistant to MRA-CN compared with parental cells. The resistant cell line also displayed 2-fold resistance to 3'-(4-morpholinyl)-3'-deaminoadriamycin but was not cross-resistant to Adriamycin or chlorambucil. Uptake of MRA-CN was slightly reduced in the resistant cells compared to sensitive cells, but the distribution of the drug within the cells was unchanged. DNA interstrand cross-linking by MRA-CN was not significantly different in the sensitive and resistant cell lines, but MRA-CN was slightly less effective in inhibiting both DNA and RNA synthesis in L5178Y/MRA-CN cells compared with parental cells. NADPH cytochrome P-450 reductase activity was increased in L5178Y/MRA-CN cells compared to parental cells, while the activity of DT-diaphorase was decreased in the resistant cells. The levels of glutathione and glutathione S-transferase activity were increased in the resistant cells compared to sensitive cells; however, pretreatment of L5178Y/MRA-CN cells with buthionine sulfoximine to reduce the glutathione level did not reverse the resistance of these cells to MRA-CN. MRA-CN induced DNA fragmentation that was characteristic of apoptosis in both L5178Y and L5178Y/MRA-CN cells at equitoxic drug concentrations. However, apoptosis occurred more rapidly in L5178Y/MRA-CN cells compared with parental cells. Thus, MRA-CN induces apoptosis in L5178Y cells, and this effect may be important for the anti-tumor activity of this agent. In contrast, DNA interstrand cross-linking does not appear to be the primary mechanism responsible for the cytotoxicity of MRA-CN in these cells.
Begleiter
A
A
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Leith
M K
MK
Johnston
J B
JB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007940:Leukemia L5178 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D005982:Glutathione Transferase; D005978:Glutathione