Human Monocytes, but not Dendritic Cells Derived from Them, Are Defective in Base Excision Repair and Hypersensitive to Methylating Agents
- 1 January 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (1), 26-31
- https://doi.org/10.1158/0008-5472.can-06-3712
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 O6-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O6-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 IIIα, 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. [Cancer Res 2007;67(1):26–31]Keywords
This publication has 20 references indexed in Scilit:
- DNA Polymerase β Promotes Recruitment of DNA Ligase IIIα−XRCC1 to Sites of Base Excision RepairBiochemistry, 2005
- MGMT: its role in cancer aetiology and cancer therapeuticsNature Reviews Cancer, 2004
- Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1Oncogene, 2004
- BER, MGMT, and MMR in defense against alkylation-induced genotoxicity and apoptosisProgress in Nucleic Acid Research and Molecular Biology, 2001
- p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agentsOncogene, 1998
- Pro‐inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum‐free conditionsEuropean Journal of Immunology, 1997
- O6‐methylguanine‐DNA methyltransferase activity in breast and brain tumorsInternational Journal of Cancer, 1995
- DNA DOUBLE-STRAND BREAKS DETECTED IN INDIVIDUAL CELLSPublished by Elsevier BV ,1991
- Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agentsMutation Research, 1990
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976