PRECLINICAL DEVELOPMENT OF CAMPTOTHECIN DERIVATIVES AND CLINICAL-TRIALS IN PEDIATRIC ONCOLOGY

Although the prognosis of childhood cancers ha; dramatically improved over the last three decades, new active drugs are needed. Camptothecin s represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of t wo of these DNA-topoisomerase 1 inhibitors, ie topotecan and irinoteca n, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active a gainst several paediatric tumour xenografts. In paediatric phase I stu dies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phas e II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients ). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdomyosarcoma, neuroblastoma, peripher al primitive neuroectodermal tumour, medulloblastoma, ependymoma, mali gnant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluatio n of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as c arboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activi ty was schedule-dependent. The optimal schedule of administration is a n issue that needs to be addressed in children. In conclusion, the pre liminary results of the paediatric evaluation of camptothecin derivati ves show very encouraging results in childhood malignancies. The poten tial place of camntothecins in the treatment of paediatric malignant t umours is discussed. ((C) Society francaise de biochimie et biologie m oleculaire / Elsevier, Paris).