Topoisomerase Related Inhibitors
DNA topoisomerases are nuclear enzymes that regulate the conformational changes in DNA topology by catalyzing the breakage and rejoining of DNA strands during the normal cell cycle. They relieve torsional stress during replication and transcription. The catalytic cycle of the enzyme consists of DNA cleavage to form a covalent enzyme-DNA intermediate, DNA relaxation, and re-ligation of the phosphate backbone to restore the continuity of the DNA. Three different types of topoisomerases have been reported in humans; Type I (91-kDa monomer), Type IIα (170-kDa dimer), and Type IIβ (180-kDa dimer). Simpler organisms possess only topoisomerase I; however, higher organisms have all three types of topoisomerases. While topoisomerase IIα is present in all eukaryotes, IIβ is present only in vertebrates and appears to be closely associated with cell differentiation, but not proliferation. Topoisomerases act by catalyzing the breakdown and rejoining reactions in the phosphodiester backbone of DNA. Topoisomerase I reversibly cleaves a single strand in duplex DNA molecule, whereas topoisomerase II breaks and rejoins both DNA strands.
During the past few years topoisomerases have become important chemotherapeutic targets for cancer treatment. Several novel compounds have been developed that can target either topoisomerase I or topoisomerase IIα-/IIβ- isoforms, or all three types of topoisomerases. Inhibition of topoisomerase II is considered to be more challenging due to the complexity of interactions. Most inhibitors of topoisomerase II block the ligation step, leading to stabilized "cleavable complexes"between DNA and the enzyme. Most enzyme inhibitors function by docking into the enzyme active site or nearby allosteric site to block the reaction of the normal substrate. Inhibition of topoisomerase II involves two parts: the aromatic part of the inhibitor molecule intercalates between DNA base pairs and another more polar portion interacts with topoisomerase. Because topoisomerase II inhibitors (e.g., doxorubicin and etoposide) act as poisons rather than as classical competitive inhibitors, their action is dependent upon the level of the enzyme in cells. Rapidly proliferating cells, which contain relatively higher levels of topoisomerase II, appear to be more sensitive to these agents. On the other hand, differentiated cells have relatively low topoisomerase II levels and are much more resistant to the action of these inhibitors.
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