Clinical and preclinical pharmacology of Topotecan

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specifi c inhibitor of topoisomerase I and is endowed of potent antiproliferative e ffect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blo od vessels in many in vivo experimental models. During the last years, seve ral phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults, In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non- small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndro mes and myeloma. The clinical effectiveness of topotecan has been also demo nstrated in ovarian carcinoma, even after failure of first or second line c hemotherapy and in SCLC, where the response rate is 39%, while the percenta ge decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable , and the most frequent and severe toxicity is represented by myelosuppress ion. Leukopenia and neutropenia, which follow the administration of topotec an, are non-cumulative and self-limiting and unfrequently complicated by in fections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in polychemotherapeutic protocols.