Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model

OBJECTIVE: Intracerebral clysis is a drug delivery technique that depends o n convection-enhanced microinfusion to achieve therapeutic drug levels with in the brain, In this study, brain tumor-bearing rats were treated with top otecan delivered systemically and by the intracerebral clysis method. Our o bjective was to determine the efficacy and tissue distribution of topotecan delivered by intracerebral clysis. METHODS: The C6/Wistar rat glioma model was used after a thymidine incorpor ation assay determined topotecan sensitivity of C6 cells in vitro. Long-ter m survival of animals provided objective measurements of efficacy; records of animal weight during treatment and neurological status served to approxi mate toxicity. Topotecan tissue penetration was measured in samples of ex v ivo tumor and surrounding brain tissue with high-pressure liquid chromatogr aphy. RESULTS: Dose escalation demonstrated significant sensitivity of C6 glioma cells to topotecan (median lethal dose, 0.19 mu mol/L). Eleven of 12 rats b earing established intracerebral C6 glioma and receiving topotecan by intra cerebral clysis survived beyond the end point of 120 days; no untreated con trol or systemically treated animal survived beyond 26 days (n = 18; P < 0. 005). Histopathological assessment of animals demonstrated significant tumo r masses in the brains of intraperitoneally treated animals and untreated c ontrol animals. In contrast, no residual tumor was found in the brains of i ntracerebral clysis groups. Animal weights during treatment were markedly r educed by intraperitoneal dosing (n = 6) but not by low-dose intracerebral clysis (32 <mu>g/kg/d for 5 d; n = 6). None of the low-dose intracerebral c lysis-treated animals demonstrated neurological toxicity, and one high-dose intracerebral clysis-treated animal (160 mug/kg/d for 2 d; n = 6) died dur ing follow-up. Topotecan was detected well beyond the boundaries of the tum or and even in the contralateral hemisphere in animals treated with intrace rebral clysis. CONCLUSION: Topotecan delivered by the intracerebral clysis method is effec tive for treatment of brain tumors in the rat glioma model. These studies p rovide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules.