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Experimental Chemotherapy of Human Medulloblastoma with Classical Alkylators¹

Departments of Pediatrics [H. S. F.], Medicine [S. C. S.], Community and Family Medicine, Biometry Division [L. H. M.], and Pathology [H. S. F., S. C. S., D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; The Johns Hopkins Oncology Center [O. M. C.], Baltimore, Maryland 21205; and Department of Chemistry [S. M. L., V. L. B.], The Catholic University of America, Washington, DC 20064

Seven classical alkylators were tested for activity against the continuous human medulloblastoma cell line TE-671 grown in vitro and as s.c. and intracranial xenografts in athymic mice. Drugs tested included melphalan, cyclophosphamide (4-hydroperoxycyclophosphamide in vitro), iphosphamide (4-hydroperoxyiphosphamide in vitro), phenylketocyclophosphamide, phenylketoiphosphamide, Asta Z 7557, and thiotriethyl-enephosphoramide. All agents were active, with melphalan demonstrating the most activity in vitro and in vivo. Comparative studies of cyclophosphamide and phenylketocyclophosphamide revealed partition coefficients (log P) of 0.73 and >1.69, respectively, and cyclophosphamide exhibited greater cytotoxic activity in post- (equitoxic) drug administration murine plasma. Hematological toxicity was limited to leukopenia/neutropenia for both of these agents. These studies suggest that the classical alkylators may have a role in the treatment of medulloblastoma and provide a means to further analyze their therapeutic potential.

¹ This work was supported by NIH Grants 1 PO1 NS20023-01 and RO1-NS20581.

² Recipient of an American Cancer Society Junior Clinical Faculty Fellowship, an Association for Brain Tumor Research Fellowship in memory of Bryce Davis, and an NINCDS Teacher-Investigator Award (K07 NS00958-01). To whom requests for reprints should be addressed, at Department of Pediatrics, Division Hematology-Oncology, Duke University Medical Center, Durham, NC 27710.

Received 11/19/85. Revised 2/13/86. Accepted 2/28/86.

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