RESPONSE OF BRAIN-TUMORS TO CHEMOTHERAPY, EVALUATED IN A CLINICALLY RELEVANT XENOGRAFT MODEL

Chemotherapy for brain tumors remains unsatisfactory. Despite increasi ng participation in clinical trials, there is a clear need for pre-cli nical models. Heterotransplantation of surgical specimens directly int o the anterior chamber of the nude mouse eye has been demonstrated to produce evaluable xenografts. Drug access in this model is considered to mimic the blood-brain barrier. Five clinical specimens in 3 childre n with primitive neuroectodermal tumor/medulloblastoma were the source s of 293 intraocular xenografts (5 cohorts by source). Each tumor-bear ing mouse received 1 of 5 drugs or normal saline, by intraperitoneal i njection, weekly for 5 weeks. Response was monitored for up to 22 week s, using a staging system which estimates the proportion of the anteri or chamber filled by tumor. Results were analysed both as response rat es (shrinkage in excess of 50%) at the conclusion of the treatment cou rse and as time to tumor progression by the life table method. Compari son of response rates within cohorts by source of xenografts (exact ch i-square test for overall and 2-sided Fisher's exact test for paired c omparisons) indicated cyclophosphamide to be the most effective single agent. In logrank analyses cyclophosphamide achieved significantly lo nger delays to progression than all other drugs in one cohort and long er delays than all but diaziquone in 2 other cohorts. The intraocular xenograft model is a clinically relevant system for the study of thera peutic agents in brain tumors. The effectiveness of intensive dosage c yclophosphamide in a model dependent on access across the blood-aqueou s barrier is important and consistent with recent clinical data.