Objective. The topoisomerase I (topo-I) enzyme is a crucial element of the cellular replication machinery because of its role in controlling and modifying DNA topology. The topo-I directed agents, topotecan (TPT) and irinotecan (IRN) interact with the enzyme-DNA complex resulting in double-strand breaks. This mechanism of action suggests that topo-I inhibitors induce cell death only when DNA synthesis is under way. It is therefore important to consider this mechanism of action in the clinical development of these compounds. With the aim of maximizing the antitumor effect of TPT and IRN, we have investigated different schedules of administration of TPT and IRN in preclinic and clinic models. Methods. In a first phase, TPT and IRN were administered in different doses and schedules in immunodeficient mice bearing xenografts of pediatric solid tumors. Once the most effective schedules of administration were identified, phase I and phase II studies were carried out in children. Results. In the xenograft model, the antitumor activity is highly dependent of the dose and schedule of administration. For equivalent cumulative doses, the antitumor effect was more greater when TPT and IRN were administered at low doses, in protracted schedules of daily administration. The schedule of daily administration for five days a week for two consecutive weeks [(qd×S)×2] was further developed in clinical studies. The phase I studies defined the maximum tolerated dose and confirmed the spectrum of sensitivities shown in the xenograft model. Phase II studies of TPT are currently under way in patients with neuroblastoma, rhabdomyosarcoma and medulloblastoma; and phase II studies of IRN in patients with rhabdomyosarcoma, osteosarcoma, glioma and colorectal carcinoma. Conclusions. The xenograft models are useful predictors of response of pediatric malignancies to the topo-I inhibitors. The decrease in the dose intensity, administering the same total dose over a more prolonged period of time, offers a therapeutic advantage, probably my maximizing the formation of covalent complexes between topo-I and DNA. The schedule [(qd×5)×2] has been selected for future clinical studies.
|Translated title of the contribution||Model for the development of antineoplastic drugs in pediatrics: Direct translation of a preclinical model to the clinic|
|Number of pages||7|
|State||Published - Jan 1 2001|
- Pediatric cancer
- Topoisomerase I
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health