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, phenylketocyclophosphamide, thiotepa, 1,3-bis(2-chloroethyl)-1-nitrosourea (in vivo), and busulfan (in vivo). Melphalan and phenylketocyclophosphamide 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 microM for melphalan and 4.60, 5.01, and 4.34 microM for phenylketocyclophosphamide against TE-671, D283 Med, and Daoy, respectively. Melphalan, cyclophosphamide, 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)-1-nitrosourea or busulfan. Melphalan, cyclophosphamide, 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 antitumor activity of nitrogen and phosphoramide mustard-based bifunctional 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.
Friedman
H S
HS
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Colvin
O M
OM
Skapek
S X
SX
Ludeman
S M
SM
Elion
G B
GB
Schold
S C
SC
Jacobsen
P F
PF
Muhlbaier
L H
LH
Bigner
D D
DD
D000477:Alkylating Agents / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002460:Cell Line; D003432:Cross-Linking Reagents; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents