Topotecan (9-dimethylaminomethyl-10-hydroxycamptothecin) is a novel semi-sy
nthetic water-soluble derivative of camptothecin that inhibits the intranuc
lear enzyme topoisomerase I. Preclinical data showed that topotecan had imp
ressive antitumor activities against a variety of adult and pediatric tumor
s. Specifically tumor regressions have been reported in ependymoma, medullo
blastoma, and high-grade glioma xenografts after protracted topotecan admin
istration. Moreover, topotecan has shown activity against tumors metastatic
to the central nervous system (CNS) tumors. Thus, topotecan has great pote
ntial for treating primary and metastatic CNS malignancies, and the present
study was conducted to evaluate the penetration of topotecan into cerebros
pinal fluid (CSF) of children with recurrent tumors. Data from the nonhuman
primate model given topotecan as a short bolus showed that the average top
otecan CSF penetration was 32% (range 29-37%), We evaluated the degree of t
opotecan lactone penetration after a 30-min, 24-hour, and 72-hour infusion.
The average CSF penetration for both topotecan lactone and hydroxy acid wa
s similar among the three groups (similar to 40%), and although slightly gr
eater in the 72-hour group (similar to 58%) the difference was not statisti
cally 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, al
though topotecan lactone penetrates well into ventricular CSF, its concentr
ation in the lumbar fluid is much less, which may be clinically relevant de
pending upon the site and histology of the tumor.