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Experimental Chemotherapy of Human Medulloblastoma Cell Lines and Transplantable Xenografts with Bifunctional Alkylating Agents¹

Departments of Pediatrics [S. X. S., H. S. F.], Medicine [G. B. E, S. C. S.], Community and Family Medicine, Biometry Division [L. H. M.], and Pathology [D. D. B., H. S. F., S. C. S.], and the Preuss Laboratory for Brain Tumor Research [D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; the Johns Hopkins Oncology Center, Baltimore, Maryland 21205 [O.M.C.]; the Department of Chemistry, The Catholic University of America, Washington, DC 20064 [S. M. L.]; and the Department of Neuropathology, Royal Perth Hospital, Perth, Western Australia 6001 [P. F. J.]

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 µM for melphalan and 4.60, 5.01, and 4.34 µM 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.

¹ This work was supported by NIH Grants CA11898, CA44640, 1 NINCDS NS 20023, 1 K07 NS 00958, NS 20581, and CA 37323.

² To whom requests for reprints should be addressed at P.O. Box 2916, Department of Pediatrics, Division of Hematology/Oncology, Duke University Medical Center, Durham, NC 27710.

Received 9/21/87. Revised 2/15/88. Accepted 4/25/88.

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