Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience.

Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisynthetic product derived from camptothecin, which was discovered during a National Cancer Institute cytotoxic drug screening program almost 30 years ago. It acts by forming a stable covalent complex with the DNA/topoisomerase I aggregate, the so-called 'cleavable complex'. This process leads to breaks in the DNA strand resulting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake and a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lactone form to the open ring inactive carboxylate form. It is also able to penetrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impaired. In contrast, pharmacokinetic behavior is unchanged in patients with limited hepatic function. The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as 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/m2 topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical 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 topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.