Topoisomerases carry out the important function of unwinding DNA by creating temporary breaks in DNA, promoting passage of single strands of DNA through breaks, and then resealing the breaks. This function is critical in allowing access of repair and replication complexes to linear strands of DNA. Similar enzymes are found throughout the eukaryotic and prokaryotic world, a testament to their essential function. Likewise, they are one of the most common targets of naturally occurring poisons. Two classes of topoisomerases (topos) are found in human cells: topo I does not require ATP for strand breakage and resealing, and creates single strand breaks, while the several isoforms of topo II require ATP and create double strand breaks.
TOPOISOMERASE I INHIBITORS: CAMPTOTHECINS
The camptothecins are inhibitors of topo 1 with broad activity against epithelial cancers. Camptothecin was isolated from the Chinese tree Camptotheca acuminata in 1966 and had potent antitumor effects in animal systems. Topotecan (Hycamptin) and irinotecan (Camptosar), two synthetic agents in this class, have been subsequently approved for clinical use in the United States. Topotecan is currently used as second-line chemotherapy for ovarian cancer and small cell lung cancer (SCLC). Irinotecan is indicated for the treatment of metastatic colon cancer, both in first-line and salvage combination therapy, and has been incorporated into regimens to treat small cell lung cancer, gynecologic, and upper gastrointestinal malignancies.
The camptothecins consist of a five-ring structure in which a quinolone moiety is joined to a terminal α-hydroxy-δ-lactone ring (Figure 4-1). The electrophilic center of the lactone subunit is responsible for the camptothecins’ biological activity. At the same time, the lactone is also vulnerable to reversible hydrolysis to a less active carboxylate species at neutral and alkaline pH. Substitutions on the C-9 and C-10 positions on the quinolone ring stabilize the lactone and enhance antitumor activity by preventing its conversion to the inactive carboxylate form in human blood and tissues (1).
Structure of the camptothecins.
Camptothecin and its analogs exert their antitumor activity by inhibiting the enzyme DNA topo I, a nuclear enzyme that relieves torsional strain in supercoiled DNA during replication, repair, and transcription (Figure 4-2). The enzyme forms a transient, intermediate complex with single-stranded DNA that opens the DNA strand and allows passage of an intact single strand through the nick. The strand break also allows for rotation about the intact strand. Camptothecins bind to and stabilize the otherwise transient DNA-enzyme complex and prevent resealing of the broken strand. The single strand break, when it encounters a replication complex, leads to a double-stranded break, and an accumulation of double strand breaks leads to apoptosis. Active synthesis of DNA is a prerequisite for this interaction (1). In addition ...