ISSN:
1573-0646
Keywords:
cytotoxicity
;
DNA cleavage
;
VP-16
;
aclarubicin
;
antagonism
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary In previous studies, we found that VP-16 (etoposide) induced cytotoxicity and protein-concealed strand break formation was prevented in a small cell lung cancer (SCLC) cell line, when the cells were incubated with aclarubicin prior to treatment with VP-16. In the present work, we studied the effect of adding aclarubicin to the cell suspension after VP-16. In a clonogenic assay, we found that the cytotoxicity induced by VP-16 in SCLC cells was inhibited when cells were postincubated with aclarubicin. The addition of aclarubicin at any time in relation to VP-16 was able to stop further cytotoxicity induced by the topoisomerase II (topo-II) targeting drug. Aclarubicin was also found to antagonize the cytotoxicity induced by VM-26 (teniposide), and m-AMSA. With the alkaline elution technique we found that postincubating the cells with aclarubicin inhibited VP-16-induced DNA strand break formation. In anin vitro system with purified topo-II and naked DNA we likewise found, that postincubation with aclarubicin prevented VP-16 induced cleavage. In the samein vitro system, also baseline cleavage induced by topo-II was inhibited when aclarubicin was present. Importantly, aclarubicin exerted the antagonism to topo-II targeting drugs both when administered prior to and after the topo-II targeting agents. Thus, our data suggest that sequential rather than simultaneous administration of aclarubicin and topo-II targeting agents may be superior with respect to net-cytotoxicity. In conclusion, our results support the notion that aclarubicin interferes with steps prior to the formation of the cleavable complex in the catalytic cycle of topo-II, and further that the antagonism of aclarubicin on the effect of topo-II targeting drugs may be due to a decrease in the initial noncovalent binding of topo-II to DNA.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00873043
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