Topoisomerase Inhibitor-Based Cancer Drugs

The topoisomerases are essential nuclear enzymes for DNA replication. They control DNA structure by maintaining the correct superhelical state within the cell, as well as by resolving intertwined DNA strands. This requires the formation of transient breaks in DNA. Topoisomerase I generates single-stranded breaks, and topoisomerase II introduces double-stranded breaks.

The topoisomerase inhibitors are termed topoisomerase poisons because they convert their enzyme into a potent cellular toxin by preventing DNA from unwinding and interfering with the cell's replication, leading to cell death. All cells require topoisomerases, but fast-growing cancer cells need more of them. By inhibiting the enzymes, the drugs selectively inflict more damage on cancer cells than on normal cells.

Camptothecins and their derivatives are substrates of topoisomerase I. CT-2106 is a polyglutamate-camptothecin. Linking a camptothecin to polyglutamate polymer renders it water soluble, and studies suggest that it permits up to 400% more drug to be administered without an increase in toxicity.Campto (Irinotecan), a topoisomerase I inhibitor, is a reference treatment for advanced colorectal cancer.

Rubitecan, a topoisomerase I inhibitor, is an analogue of camptothecins. Hycamtin (Topetecan) is a semi-synthetic derivative of camptothecin. Pegamotecan (Prothecan) is a PEG-enhanced version of camptothecin.

Novantrone is a potent inhibitor of topoisomerase II. Lucanthone is a topoisomerase II inhibitor and has marked radiosensitizing activity in advanced brain tumors in humans.

MLN576 (XR11576) is a small molecule with DNA-targeting activity that includes dual inhibition of topoisomerases I and II.