The resistance of medulloblastoma to current therapy is a multifactorial process, due in part to the heterogeneity of this tumor, the lack of an appropriate system to identify active compounds, and the potentially limited access of active compounds to the tumor site. These studies are designed to utilize our in vitro/in vivo models for human medulloblastoma to enhance an understanding of this tumor and its response to single and combination therapy.
The specific aims are: 1) to use our present models of human medulloblastoma (TE-671 and D283 Med) and additional ones we will establish to study the in vitro and in vivo response of this tumor to chemotherapeutic agents (particularly classical alkylators and agents altering glutamine and glutamate metabolism) and radiation, determining the classes, properties and schedules of the most effective compounds; 2) to use these results to evaluate combination and combined modality therapy of human medullolastoma; 3) to apply these results to clinical trials. In vitro studies will be performed by using a double layer soft agar clonogenic assay to study sensitivity of the human medulloblastoma cell lines to chemotherapeutic agents and radiation. In vivo studies will be performed by studying the sensitivity of the cell lines growing subcutaneously or intracranially in nude athymic mice or rats. Subcutaneously growing tumors will be treated when the median tumor volume exceeds 200 mm3. Chemotherapeutic agents will be given i.p. at the LD10. Radiation therapy will be performed on a 60Co unit. Response will be assessed by comparing growth delay, per cent regressions, and tumor volume ratios between treated and untreated animals. Intracranial tumors will be treated on day 11 after tumor implantation (see enclosure) and response assessed by the comparison of median survival time and long-term survivors (greater than 60 days) between treated and control groups. These results will be used to define the therapeutic sensitivity of medulloblastoma allowing the rational design of chemotherapeutic and combined modality regimens.
Showing the most recent 10 out of 17 publications
