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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 an in vitro system with purified topo-II and naked DNA we likewise found, that postincubation with aclarubicin prevented VP-16 induced cleavage. In the same in 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.(ABSTRACT TRUNCATED AT 250 WORDS)
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
March 1999,
Biochemistry. Biokhimiia,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
January 1991,
Anticancer research,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
January 2019,
Frontiers in molecular biosciences,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
December 2010,
Toxicological sciences : an official journal of the Society of Toxicology,
L N Petersen, and
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B S Sørensen, and
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M Spang-Thomsen
February 2017,
The EMBO journal,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
September 2003,
Mutation research,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
December 1989,
Hiroshima journal of medical sciences,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
July 1985,
Biochemical pharmacology,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
July 1987,
Biochemistry,
L N Petersen, and
P B Jensen, and
B S Sørensen, and
S A Engelholm, and
M Spang-Thomsen
July 1989,
Biochemistry,
