INTRATUMORAL INFUSION OF TOPOTECAN PROLONGS SURVIVAL IN THE NUDE RAT INTRACRANIAL U87 HUMAN GLIOMA MODEL

Topotecan is a topoisomerase (topo) I inhibitor with promising activit y in preclinical studies. We hypothesized that low-dose intratumoral d elivery of topotecan would be highly effective for gliomas. Human glio ma cell lines (U87, U138 and U373) displayed different sensitivities t o topotecan (IC50 range: 0.037 mu M to 0.280 mu M) in cell culture. Th e most resistant of the glioma cell lines (U87) was implanted stereota ctically into the brains of nude rats. Twelve days later, at which tim e tumor diameter measured 2 to 2.5 mm, animals were randomized to thre e groups: group I, intratumoral topotecan infused via osmotic pump (n = 12); group II, intratumoral saline infusion (n = 7); and group III, no treatment (n = 10). Animals were sacrificed when signs of deteriora tion developed, or at 60 days. Animals in group I had a mean survival time (MST) of > 55 days (range = 40-60); whereas, those in groups II a nd III had MST of 26.1 (range = 21-31) and 26.5 (range = 20-30) days, respectively. The differences in survival between group I and each of the other groups were statistically significant (p < 0.0001; Logrank M antel-Cox). None of the animals that survived 60 days had histological evidence of residual tumor at sacrifice. Measurement of topotecan lev els in normal brain revealed cytotoxic concentrations up to 4.5 mm fro m the site of infusion. This study demonstrates that intratumoral topo tecan delivered via an osmotic pump prolongs survival in the U87 human glioma model.