Postincubation with aclarubicin reverses topoisomerase II mediated DNA cleavage, strand breaks, and cytotoxicity induced by VP-16
Research output: Contribution to journal › Journal article › Research › peer-review
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)
Original language | English |
---|---|
Journal | Investigational New Drugs |
Volume | 12 |
Issue number | 4 |
Pages (from-to) | 289-97 |
Number of pages | 8 |
ISSN | 0167-6997 |
Publication status | Published - 1994 |
Bibliographical note
Keywords: Aclarubicin; Animals; Carcinoma, Small Cell; DNA Damage; DNA Topoisomerases, Type II; DNA, Neoplasm; Etoposide; Humans; Lung Neoplasms; Mice; Time Factors; Tumor Cells, Cultured; Tumor Stem Cell Assay
ID: 12870320