DNA cross-linking and cytotoxicity of the alkylating cyanomorpholino derivative of doxorubicin in multidrug-resistant cells.
The cyanomorpholino derivative of doxorubicin (MRA-CN) is an anthracycline that is extremely potent and non-cross-resistant with doxorubicin (DOX) in multidrug-resistant cells. MRA-CN binds to and cross-links DNA and thus has been proposed to act as a targeted alkylating agent. In our study, the number of DNA interstrand and DNA-protein cross-links produced by MRA-CN was identical in multidrug-resistant Dx5 and parental MES-SA cells, as shown by alkaline elution analysis. The amount of cross-linking was directly proportional to drug concentration at concentrations from 10(-11) to 10(-7) M MRA-CN. Extensive DNA cross-linking was evident within 30 minutes of drug exposure. After 1 hour of drug exposure, the number of DNA cross-links increased for 90 minutes, reached a plateau, and then began to decrease after 120 minutes. Loss of cell viability was also observed as early as 3 hours after exposure to MRA-CN. The finding of the same number of DNA cross-links in MES-SA and Dx5 cells indicates that similar amounts of MRA-CN are likely to enter the nuclei of multidrug-resistant and sensitive cells. Other anthracyclines have major differences in nuclear distribution in sensitive and resistant cells. Several factors may contribute to the non-cross-resistance of MRA-CN in multidrug-resistant cells. (a) The lipophilicity of MRA-CN facilitates cell entry. (b) The substitution and loss of basicity at the amino nitrogen may reduce the affinity of the drug for the P-glycoprotein efflux pump, compared with that of DOX. (c) The detoxification function of P-glycoprotein may be less effective for drugs that produce rapid and irreversible cell damage, such as the DNA-targeted alkylation caused by MRA-CN.
Scudder
S A
SA
Department of Medicine, University of California, Davis, Sacramento.
Brown
J M
JM
Sikic
B I
BI
D000477:Alkylating Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D004247:DNA