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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07NS000958-03
Application #
3078380
Study Section
Neurological Disorders Program Project Review A Committee (NSPA)
Project Start
1985-04-01
Project End
1990-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Laskowitz, D T; Elion, G B; Dewhirst, M W et al. (1992) Hyperthermia-induced enhancement of melphalan activity against a melphalan-resistant human rhabdomyosarcoma xenograft. Radiat Res 129:218-23
Friedman, H S; Colvin, O M; Kaufmann, S H et al. (1992) Cyclophosphamide resistance in medulloblastoma. Cancer Res 52:5373-8
Lilley, E R; Elion, G B; Dewhirst, M W et al. (1991) Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR. Cancer Res 51:3906-9
Bigner, S H; Friedman, H S; Vogelstein, B et al. (1990) Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res 50:2347-50
Oakes, W J; Friedman, H S; Bigner, S H et al. (1990) Successful laboratory growth and analysis of CUSA-obtained medulloblastoma samples. Technical note. J Neurosurg 72:821-3
Friedman, H S; Schold Jr, S C; Djang, W T et al. (1989) Criteria for termination of phase II chemotherapy for patients with progressive or recurrent brain tumor. Neurology 39:62-6
Friedman, H S; Schold Jr, S C; Mahaley Jr, M S et al. (1989) Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma. J Clin Oncol 7:904-11
He, X M; Skapek, S X; Wikstrand, C J et al. (1989) Phenotypic analysis of four human medulloblastoma cell lines and transplantable xenografts. J Neuropathol Exp Neurol 48:48-68
Bigner, S H; Mark, J; Friedman, H S et al. (1988) Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet 30:91-101
Friedman, H S; Skapek, S X; Colvin, O M et al. (1988) Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma. Cancer Res 48:5397-402

Showing the most recent 10 out of 17 publications