Cellular and molecular pharmacology of 4'-epidoxorubicin in HeLa cells. Comparison with its parent drug, doxorubicin.
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 (24 h) 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 t1/2 of about 1.7 h. These findings underline the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytotoxic and DNA-damaging effects.
Cantoni
O
O
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Italy.
Sestili
P
P
Cattabeni
F
F
Geroni
C
C
Grandi
M
M
Giuliani
F C
FC
D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D015251:Epirubicin / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans
D004273:DNA, Neoplasm; D015251:Epirubicin; D004317:Doxorubicin