Topotecan, also known as Hycamtin, is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer. It is a semi-synthetic derivative of camptothecin (obtained from the plant Camptotheca acuminata). This molecule is an anti-tumor drug with topoisomerase I-inhibitory activity. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and DNA repairs. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers. Topotecan is believed to exert its cytotoxic effects during the S-phase of the cell cycle replication. Topotecan binds to the topoisomerase I-DNA complex and prevents the religation of the single strand breaks and of any breaks in the DNA. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest. In consequence, this causes lethal double-stranded breaks in the DNA. The formation of this ternary complex eventually leads to apoptosis. Moreover, topotecan mimics a DNA base pair and binds at the site of DNA cleavage. Intercalation displaces the downstream DNA, thus preventing the religation of the cleaved strand.

Topotecan Pathway References