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M Cornarotti, S Tinelli, E Willmore, F Zunino, LM Fisher, CA Austin and G Capranico
Divisione di Oncologia Sperimentale B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Effective anticancer agents, such as epipodophyllotoxins and anthracyclines, exert their antitumor activity through stabilization of cleavable topoisomerase II/DNA complexes, which may result in DNA breakage on detergent addition. Two isozymes (alpha and beta) of DNA topoisomerase II are present in human cells; however, their roles as drug targets have not been completely defined. We determined the in vitro isoenzyme sensitivities to VM-26 (teniposide) and 4-demethoxy-3'- deamino-3'-hydroxy-4'-epi-doxorubicin (an anthracycline analog) and established the sequence selectivity of isoenzyme-mediated DNA cleavage. Human topoisomerases IIalpha and IIbeta were purified from yeast cells overexpressing the corresponding plasmid-borne cDNA. Enzyme sensitivities to drugs were measured by a DNA cleavage assay using 32P- labeled simian virus 40 DNA fragments, and cleavage sites were mapped using agarose and sequencing gels. Both isozymes were sensitive to the studied poisons. They stimulated similar cleavage intensity patterns in agarose and sequencing gels; however, minor differences could be detected. The results showed that local base preferences for DNA cleavage without drugs were different at positions -2 and -1. On the other hand, sequence specificities of VM-26 and 4-demethoxy-3'-deamino- 3'-hydroxy-4'-epi-doxorubicin were identical for both isozymes and corresponded to those of the native murine enzyme. The identical drug sequence specificities suggested that molecular interactions of the tested drugs in the ternary complex are likely similar between the two isozymes. The current findings indicate that both topoisomerase IIalpha and IIbeta may be in vivo targets of antitumor poisons.
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