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Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR)

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Purpose: We have previously reported preferential repair of DNA interstrand crosslinks in the 4-hydroperoxycyclophosphamide-resistant human medulloblastoma cell line D-283 Med (4-HCR). We now report further studies that explored the potential mechanisms underlying this repair. Methods: Limiting dilution assays and Western, Southern, and Northern blots were used to compare specific differences between D-283 Med (4-HCR) and its parental line D-283 Med. Results: D-283 Med (4-HCR) was cross-resistant to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with O 6-alkylguanine-DNA alkyltransferase (AGT) levels of 466 ± 164 fmol/mg protein; AGT levels in the parental line, D-283 Med, were 76 ± 96 fmol/mg. The increase in AGT activity was not a result of gene amplification. Depleting AGT with O 6-benzylguanine partially restored sensitivity to BCNU. Both cell lines were deficient in the human mismatch protein MutLα. ERCC4 mRNA and poly(ADP-ribose) polymerase levels were similar in both cell lines, and ERCC1 mRNA levels were 2- to 2.5-fold lower in D-283 Med (4-HCR). Topoisomerase I levels were 2- to 2.5-fold higher in D-283 Med compared with D-283 Med (4-HCR). Conclusion: These results, while illustrating the multiple differences between D-283 Med and D-283 Med (4-HCR), do not explain the enhanced DNA interstrand crosslink repair seen in D-283 Med (4-HCR).

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Received: 16 January 1998 / Accepted: 14 May 1998

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Dong, Q., Johnson, S., Colvin, O. et al. Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR). Cancer Chemother Pharmacol 43, 73–79 (1999). https://doi.org/10.1007/s002800050865

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  • DOI: https://doi.org/10.1007/s002800050865

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