[Topotecan: a new field of use]

Topotecan, a semi-synthetic derivative of the alkaloid camptothecin is an antitumor drug that like other camptothecin derivatives, targets DNA topoisomerase I, an enzyme that is present in cells in concentration relatively independent of the stage in the cell cycle. Topotecan stabilizes the complex formed between topoisomerase I and DNA, leading to DNA strand breakage and cell death. In accordance with preclinical studies, clinical efficacy of topotecan was documented in ovarian carcinoma, in small cell lung cancer and in childhood solid tumors. Myelosuppression is the dose-limiting toxicity and nonhematologic side effects are generally mild. The activity of topotecan against a number of hematological malignancies is now increasingly exploited as well as its role in high-dose chemotherapy programs with stem cell support. In both lymphoblastic and myeloid acute leukemias, topotecan has been widely utilised both as single agent or associated to other cytostatic drugs with proven efficacy in these diseases. Most of the published phase II studies demonstrated that heavily pre-treated, relapsing patients achieve a high percentage of overall responses with manageable toxicity. In myelodisplastic syndromes and acute myelomonocitic leukemias a recently published study shows positive results for the combination of topotecan and cytarabin. Topotecan seems to preferentially affect the abnormal cytogenetic clones and in patients achieving a complete response, a conversion from an aneuploid to a diploid karyotipe was documented. In non-Hodgkin lymphomas, several schedules have been tested in the phase I setting. When utilized alone and at very low dosage, the drug yielded 15% of objective responses and a lack of extrahematologic toxicity. Of particular interest seems to be the association of topotecan with taxanes that needs to be supported by growth factors. In multiple myeloma Topotecan has been utilized as single agent in heavily pre-treated patients. The obtained results show good activity and again myelosuppression as preminent toxicity. The use of topotecan in high-dose chemotherapy regimens for multiple myeloma has been proposed. The utilization of topotecan in high-dose chemotherapy is one of the newer and more interesting applications. Solid tumors (i.e. ovarian cancer and small cell lung cancer) are actually investigated by many authors, who have indicated that this drug can be used preferentially as a part of diversified programs containing overlimit dosages of different cytostatics. Furthermore, topotecan demonstrated to be an effective drug to mobilize CD34+ cells for autografting. A general conclusion is that topotecan is an interesting addition to the actual chemotherapy scenario, both because of its mechanism of action and its toxicity profile. The present review of the new possibility of utilization, give us the idea that topotecan has activity in several hematologic neoplasias; further investigations in these diseases (i.e., induction treatment, combination chemotherapy) are then warranted. The broad spectrum of antitumor activity and the characteristics of toxicity make it also interesting for use in both the circulating progenitor cell mobilization and in the consolidation phase of high-dose chemotherapy programs.