Altered topoisomerase I and II activities in suramin-resistant lung fibrosarcoma cells.
To better understand the molecular basis for the cytotoxic effects of suramin, we have developed suramin-resistant DC-3F/SU 1000 cells by continuous exposure of fibrosarcoma cells to increasing concentrations of suramin. The suramin resistance (approximately 10-fold) is not associated with changes in uptake or intracellular distribution of the drug. The sensitivity to actinomycin D, cytarabine, aphidicolin, hydroxyurea, vincristine, and 5-fluorouracil is unaltered. In contrast, DC-3F/SU 1000 cells are about 2-fold resistant to classical DNA topoisomerase II inhibitors such as doxorubicin, amsacrine, and etoposide, whereas the cells are 1.5-fold more sensitive to the topoisomerase I inhibitor camptothecin. The cross-resistance to topoisomerase II inhibitors occurred earlier than the collateral sensitivity to camptothecin. Amsacrine- and etoposide-induced DNA-protein complex formation is reduced about 2-fold in DC-3F/SU 1000 cells, compared with DC-3F cells, whereas camptothecin-induced DNA-protein complex formation is increased 1.5-fold. Western blot analysis of cellular lysates from the two cell lines shows no significant differences in the level of topoisomerase II, whereas the level of topoisomerase I is increased 2.5-fold in DC-3F/SU 1000 cells. The catalytic activities of topoisomerases I and II in nuclear extracts from DC-3F/SU 1000 cells are both about 2-fold higher than those in extracts from DC-3F cells, whereas amsacrine- and etoposide-induced DNA-protein complex formation is comparable between the two cell lines. Taken together, our results support the involvement of DNA topoisomerases in the cytotoxic activity of suramin. We further believe that the DC-3F/SU 1000 cells may be a useful model for the elucidation of factors that lead to low, clinically relevant, levels of resistance to topoisomerase II inhibitors.
Lelièvre
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Department of Structural Biology and Pharmacology, CNRS URA 147, Institute Gustave Roussy, Villejuif, France.
Benchokroun
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Y
Larsen
A K
AK
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009363:Neoplasm Proteins / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology*
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D013498:Suramin; D005047:Etoposide; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin