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A wide variety of enzymes and proteins are required to carry out all of the functions necessary to process, maintain, replicate and repair DNA. Since the integrity of DNA is critical to the survival of cancer cells, inhibiting the function of many of these proteins can theoretically provide a cytotoxic result. Once such group of enzymes that is involved in maintaining DNA topology is the topoisomerases. There are two major types of topoisomerases known as toposomaerase I and II. Each type catalyzes a unique reaction. DNA topoisomerase I is responsible for releiving torsional stress on DNA, which may accumulate during the cell cycle. Specifically, Topo I causes a single strand break and allows the second DNA strand to pass through the complex, causing an unwinding effect. Some malignant cells have increased levels of Topo I making it an attractive anticancer drug target. In fact, drugs such as topotecan and irinotecan bind to the cleavable complex, which results in an accumulation of single strand breaks. If unrepaired, these DNA strand breaks ultimately lead to cell cycle arrest and death. Topoisomerase I inhibitors: Irinotecan (Camptosar) Topotecan (Hycamtin)
Mammalian DNA Topoisomerase II exists in an alpha and beta, each located on a different chromosome. The Topo II enzyme is capable of decatenating DNA and organizing it for cell division. In contrast to Topo I, the DNA Topo II enzyme catalyzes double-strand breaks in DNA. Anticancer drugs such as etoposide bind to this cleavable complex and cause an accumulation of double strand breaks. This damage eventually causes cells to arrest and die. The epipodophyllotoxins, etoposide and teniposide, are two active anticancer drugs that inhibit Topo II activity. The anthracyclince antibiotics (doxorubicin, daunorubicin, epirubicin and idarubicin) are also believed to inhibit Topo II activity. Mitoxantron is related to anthracyclines, but what specifically developed to circumvent the toxicity associated with anthracycline therapy.
Topoisomerase II inhibitors: Etoposide (Vespid) Teniposide (Vuman)
Anthracyclines: Daunorubicin (Cerubidine) Doxorubicin (Adriamycin) Liposomal Doxorubicin (Doxil) Idarubicin (Idamycin) Epirubicin (Ellence) Mitxantrone (Novantrone) Dactinomycin (Cosmegan) Valrubicin (Valstar) |
