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Methylator Resistance Mediated by Mismatch Repair Deficiency in a Glioblastoma Multiforme Xenograft¹

Departments of Pediatrics [H. S. F., S. P. J., Q. D., S. K., S. M.], Pathology [H. S. F., B. K. A. R., S. H. B., D. D. B.], and Medicine [H. S. F., O. M. C.], Department of Biochemistry [J. T. D., P. M.], Duke University Medical Center, Durham, North Carolina 27710; Department of Experimental Pediatrics. M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030 [F. A-O.]; Department of Medicine, University of Chicago, Chicago Illinois 60637 [E. D.]; Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [P. H., G. G.]; and Department of Neurology, Southwestern Medical Center, Dallas, Texas 75325 [S. C. S.]

A methylator-resistant human glioblastoma multiforme xenograft, D-245 MG (PR), in athymic nude mice was established by serially treating the parent xenograft D-245 MG with procarbazine. D-245 MG xenografts were sensitive to procarbazine, temozolomide, N-methyl-N-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, 9-aminocamptothecin, topotecan, CPT-11, cyclophosphamide, and busulfan. D-245 MG (PR) xenografts were resistant to procarbazine, temozolomide, N-methyl-N-nitrosourea, and busulfan, but they were sensitive to the other agents. Both D-245 MG and D-245 MG (PR) xenografts displayed no O⁶-alkylguanine-DNA alkyltransferase activity, and their levels of glutathione and glutathione-S-transferase were similar. D-245 MG xenografts expressed the human mismatch repair proteins hMSH2 and hMLH1, whereas D-245 MG (PR) expressed hMLH1 but not hMSH2.

¹ This work was supported by NIH Grants CA 23099, CA 16783, CA 71627, NS 30245, NS 20034, and GM 45190.

² To whom requests for reprints should be addressed, at Duke University Medical Center, Department of Pediatrics, Box 3624, Durham, NC 27710, Phone: (919) 684-8722; Fax: (919) 684-8918.

Received 1/23/97. Accepted 5/ 7/97.

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