Inhibiting Topoisomerase I, an Emerging Treatment for Primary CNS Malignancies

High grade primary CNS gliomas hold some of the worst prognoses of any malignancy, with the vast majority of patients dying within two years of diagnosis, even with aggressive modern treatments. Surgical resection and radiotherapy are cornerstones of treatment when possible. In spite of many years of research, only recently has management with chemotherapy been able to prolong survival in patients with high grade gliomas, albeit only modestly at best. Topoisomerase I (TOP1) inhibitors target an enzyme critical for DNA replication and cell-cycle progression; they cross the blood-brain barrier and have antitumor activity against glioblastoma cells in vitro. The most frequently associated toxicities are neutropenia and diarrhea, but are often manageable. The two most used agents are irinotecan and topotecan. Due to enhanced cytochrome CY3A4/5 enzyme activity, irinotecan dose must be adjusted with concomitant enzyme-inducing antiepileptic drug usage; the data is less clear regarding the effects on topotecan. Clinical trials in patients with recurrent malignant glioma have evaluated TOP1 inhibitors as monotherapy and in combination with other agents. There is evidence for using topotecan with radiotherapy. Irinotecan has limited efficacy as monotherapy, but shows promise in combination with other agents, particularly temozolomide and bevacizumab. Newer generation TOP1 inhibitors are currently being evaluated in phase I trials. TOP1 inhibitors show promising activity in patients with primary CNS malignancies and warrant further study.

Keywords: Bevacizumab, glioblastoma, irinotecan, malignant glioma, topoisomerase, topotecan topoisomerase, CNS, brain tumor.