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Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology
G Vassal1, C Pondarré, I Boland
1Laboratory of Pharmacotoxicology and Pharmacogenetics (URA CNRS 147), Villejuif, France.
Abstract:
Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase 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 rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant 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 evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.
Insights
New DNA-topoisomerase I inhibitors, topotecan and irinotecan, show promising activity in childhood cancers. Further research is needed to optimize their administration schedules for effective paediatric oncology treatment.
Area of Science:
- Paediatric Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Childhood cancer survival has improved, but novel drugs are essential.
- Camptothecins are a promising class of anticancer agents for paediatric use.
- DNA-topoisomerase I inhibitors like topotecan and irinotecan are under investigation.
Purpose of the Study:
- To review the preclinical and clinical results of topotecan and irinotecan in paediatric malignancies.
- To evaluate the antitumour activity and safety of these camptothecin derivatives in children.
- To discuss the potential role of camptothecins in treating childhood cancers.
Main Methods:
- Review of preclinical data from paediatric tumour xenografts.
- Analysis of Phase I and Phase II clinical trial results for topotecan.
- Evaluation of ongoing clinical trials for irinotecan in children.
Main Results:
- Topotecan demonstrated activity against paediatric tumour xenografts and showed efficacy in neuroblastoma and rhabdomyosarcoma.
- Myelosuppression was the dose-limiting toxicity for topotecan in Phase I studies.
- Irinotecan exhibited broad-spectrum activity in preclinical models, with some tumour-free survivors observed.
- The activity of both drugs is schedule-dependent, requiring further optimization for paediatric administration.
Conclusions:
- Camptothecin derivatives show encouraging preliminary results in childhood malignancies.
- Topotecan and irinotecan represent a potential new treatment option for paediatric cancers.
- Further clinical evaluation is necessary to establish optimal dosing and schedules for these agents in children.