title: Human monocytes, but not dendritic cells derived from them, are defective in base excision repair and hypersensitive to methylating agents.
abstract: Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N'-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O(6)-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O(6)-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIalpha, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression.
authors.affiliation: Department of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Briegert
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009153:Mutagens / Q000494:pharmacology; D000077204:Temozolomide
chemical_list: D000477:Alkylating Agents; D009153:Mutagens; D008769:Methylnitronitrosoguanidine; D003606:Dacarbazine; D008741:Methyl Methanesulfonate; D000077204:Temozolomide