Experimental Chemotherapy of Human Medulloblastoma Cell Lines and Transplantable Xenografts with Bifunctional Alkylating Agents

A series of bifunctional alkylators were tested against the genotypically and phenotypically heterogeneous continuous human medulloblastoma cell lines, TE-671, Daoy, and D283 Med in vitro and against TE-671 and Daoy growing as s.c and intracranial xenografts in athymic mice. Drugs tested included melphalan, cyclophosphamide, iphosphamide, phenylketocydophosphamide, thiotepa, 1,3-bis(2-chloroethyl)-1-nitro- (in vivo) and busulfan (in vivo). Melphalan and phenylketocyclo-phosphamide were the most active agents in vitro with drug doses at which there is a 90% reduction in the number of colonies in comparison to controls of 2.13,5.29, and 4.72 μM for melphalan and 4.60,5.01, and 434 μM for phenylketocyclophosphamide against TE-671, D283 Med, and Daoy, respectively. Melphalan, cydophosphamide iphosphamide, phenylketocyclophosphamide and thiotepa produced significant growth delays against s.c. TE-671 and Daoy xenografts, while no activity could be demonstrated for 1,3-bis(2-chloroethyl)-l -nitrosourea or busuffan. Melphalan, cydophosphamide iphosphamide, and thiotepa also produced significant increases in median survival in mice bearing intracranial TE-671 and Daoy xenografts. These results extend our previous studies demonstrating the andtumor activity of nitrogen and phosphoramide mustard-based bifimctional alkylating agents in the treatment of human medulloblastoma continuous cell lines and transplantable xenografts, and support the continued use of these agents in clinical trials.