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T Khelifa, MR Casabianca-Pignede, B Rene and A Jacquemin-Sablon
URA 147 CNRS, Unite de Biochimie-Enzymologie, Institut Gustave Roussy, Villejuif, France.
Chinese hamster lung cells resistant to 9-OH-ellipticine, i.e., DC-3F/9- OH-E cells, are several hundredfold resistant to DNA topoisomerase II inhibitors. According to previous studies, this resistance is associated with reduced topoisomerase II activity (about 4-fold) and decreased capacity of the topoisomerase II inhibitors to induce stabilization of the cleavable complex (about 10-fold). In the present work, an antibody was raised against a fragment of human topoisomerase II alpha. This antibody, which recognizes both isoforms, was used to determine the amounts of topoisomerases II alpha and beta in the sensitive and resistant cells. Northern and immunoblot analyses showed that (i) in the parental DC-3F cells the alpha enzyme is about 20-fold more abundant than the beta enzyme and the enzyme isoforms undergo reciprocal regulation during the cell growth phases, with the expression of the alpha enzyme dropping at the plateau phase while the expression of the beta enzyme increases, and (ii) in the resistant cells the amount of alpha enzyme is about 4-5-fold smaller than that in the sensitive cells, whereas the beta enzyme is almost undetectable. Analysis of DNA restriction sites in several independently selected resistant subclones revealed some rearrangements in the beta gene in two clones. However, these gene alterations did not correlate with changes in the resistance level. The relative contribution of these different changes to the resistance phenotype is discussed.
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