Summary
The effects on cellular DNA and cytotoxicity produced by doxorubicin (Dx) and its epimer 4′-epidoxorubicin (4′E-Dx) were investigated in cultured HeLa cells. 4′E-Dx was 2.3 times more cytotoxic than Dx after 1 h of treatment, but the two anthracyclines were equally cytotoxic on longer-term (24h) drug exposure. The different kinetics of cell lethality were related to pharmacodynamic differences between the two drugs. In fact, cellular uptake and efflux rates of 4′E-Dx were faster than those of Dx on 1 h of drug exposure but similar after 24 h of treatment. 4′E-Dx caused more protein-concealed strand breaks in DNA (single and double) than did Dx, despite a lower potency for free-radical formation. The degree of strand breakage by 4′E-Dx was not a linear function of exposure time and, in fact, the rate of strand-break induction declined continuously with time. In contrast, Dx caused an almost linear increase in DNA single-strand breaks with time during 1 h of drug exposure; this was apparently due to its slower uptake. There was little repair of the DNA single-strand breaks produced by Dx upon postincubation for 5 h in a drug-free medium, whereas DNA lesions caused by 4′E-Dx were removed with a t 1/2 of about 1.7h. These findings underline the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytotoxic and DNA-damaging effects.
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Abbreviations
- DX:
-
doxorubicin
- 4′E-Dx:
-
4′-epidoxorubicin
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Cantoni, O., Sestili, P., Cattabeni, F. et al. Cellular and molecular pharmacology of 4′-epidoxorubicin in HeLa Cells. J Cancer Res Clin Oncol 115, 373–378 (1989). https://doi.org/10.1007/BF00400965
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DOI: https://doi.org/10.1007/BF00400965