Topotecan (9-dimethylaminomethyl-10-hydroxycamptothecin) is a novel semi-synthetic water-soluble derivative of camptothecin that inhibits the intranuclear enzyme topoisomerase I. Preclinical data showed that topotecan had impressive antitumor activities against a variety of adult and pediatric tumors. Specifically tumor regressions have been reported in ependymoma, medulloblastoma, and high-grade glioma xenografts after protracted topotecan administration. Moreover, topotecan has shown activity against tumors metastatic to the central nervous system (CNS) tumors. Thus, topotecan has great potential for treating primary and metastatic CNS malignancies, and the present study was conducted to evaluate the penetration of topotecan into Cerebrospinal fluid (CSF) of children with recurrent tumors. Data from the nonhuman primate model given topotecan as a short bolus showed that the average topotecan CSF penetration was 32% (range 29-37%). We evaluated the degree of topotecan lactone penetration after a 30-min, 24-hour, and 72-hour infusion. The average CSF penetration for both topotecan lactone and hydroxy acid was similar among the three groups (~ 40%), and although slightly greater in the 72-hour group (~ 58%) the difference was not statistically significant due to wide interpatient variability. We also found in a small number of patients that the lumbar topotecan CSF concentrations were approximately half that of the ventricular concentration. In conclusion, although topotecan lactone penetrates well into ventricular CSF, its concentration in the lumbar fluid is much less, which may be clinically relevant depending upon the site and histology of the tumor.
- Penetration into cerebrospinal fluid
- Topoisomerase I inhibitor
ASJC Scopus subject areas
- Cancer Research