Topotecan - A novel topoisomerase I inhibitor: Pharmacology and clinical experience

Topotecan, a water-soluble analogue of camptothecin, is a newly available c ytotoxic agent wh ich acts as an inhibitor of topoisomerase I, an enzyme ne cessary for DNA replication. Topotecan is a semisynthetic product derived f rom camptothecin, which was discovered during a National Cancer Institute c ytotoxic drug screening program almost 30 years ago. It acts by forming a s table covalent complex with the DNA/topoisomerase I aggregate, the so-calle d 'cleavable complex'. This process leads to breaks in the DNA strand resul ting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake an d a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lac tone form to the open ring inactive carboxylate form. It is also able to pe netrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impair ed. In contrast, pharmacokinetic behavior is unchanged in patients with lim ited hepatic function. The principal toxicity of topotecan when administere d at standard doses is neutropenia, but thrombocytopenia and anemia occur a s well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m( 2) topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. O ther topotecan administration schedules are currently being investigated. P reclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However , clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotec an in small cell lung cancer and ovarian cancer patients. A randomized phas e III trial of topotecan versus paclitaxel in ovarian cancer patients pretr eated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Ac tivity of topotecan was also observed in non-small-cell lung cancer, refrac tory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, eto poside, cytarabine and paclitaxel are potential interacting partners for co mbination chemotherapy regimens. However, the best combination regimen as w ell as the optimal combination schedule have yet to be conclusively determi ned. The potential of topotecan in a variety of solid tumors, as well as it s use in combination regimens for ovarian and smalt cell lung cancer is cur rently being investigated.