Topoisomerase I inhibitors

CPT has been identified as the active constituent of an extract isolated from the Chinese Tree Camptotheca acuminata. Mechanism of action studies demonstrated that CPT stabilized co-valent adducts between genomic DNA and topoI. Early clinical studies with CPT observed anti-tumour activity in a variety of common solid tumours. However, a high rate of severe and unpredictable toxicities, including haemorhagic cystitis and gastrointestinal effects, were seen. This led to discontinuation of CPT's development.

The novelty of topoI as a cellular target for chemotherapy has resulted in the development of several analogues, such as irinotecan (CPT-11) and topotecan. Both CPT-11 and topotecan have greater aqueous solubility than CPT. Analogues of CPT with an amino group at the 9-position have enhanced activity, but are less soluble than topotecan or CPT-11. CPT and all CPT derivatives have a basic 5-ring structure. Reversible, pH-dependent non-enzymatic hydrolysis of the lactone ring of all CPT derivatives results in an open-ring carboxylate moiety. The two are in equilibrium in aqueous buffers, but the carboxylate form is a less potent inhibitor of topoI and a much less potent anti-tumour agent.

To date, two CPT analogues have received regulatory approval for use in patients with solid tumours:

♦ Topotecan (hycamtin) in Europe and the US for treatment of advanced ovarian and non-small-cell lung cancers.

♦ CPT-11 (camptosar) in patients with advanced colorectal cancer. Both agents are currently administered as a 30-90 minute infusion daily for five days every three weeks (topotecan) or weekly for four weeks, every six weeks (CPT-l1). Alternate intravenous, intraperitoneal, and oral schedules are under evaluation and demonstrate anti-tumour activity.

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