title: Clinical and biological effects of demethylating agents on solid tumours - A systematic review.
abstract: BACKGROUND
  It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours.
  
  
  METHODS
  We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted.
  
  
  RESULTS
  Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes.
  
  
  CONCLUSIONS
  Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Cancer Center Amsterdam and Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Linnekamp
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Cancer Center Amsterdam and Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Butter
authors.affiliation: Cochrane Netherlands, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands; Medical Library, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Spijker
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Cancer Center Amsterdam and Cancer Genomics Center, Amsterdam, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Cancer Center Amsterdam and Cancer Genomics Center, Amsterdam, The Netherlands; Department of Medical Oncology, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl.
authors.forename: H W M
authors.initials: HWM
authors.lastname: van Laarhoven
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D003562:Cytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use; D007107:Immune System / Q000187:drug effects; D008745:Methylation / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy; D011343:Procaine / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D006830:Hydralazine; C580831:guadecitabine; D011343:Procaine; D003562:Cytidine; D000077209:Decitabine; C009131:pyrimidin-2-one beta-ribofuranoside; D001374:Azacitidine
keywords: DNMT inhibitor; Demethylating agents; Epigenetics; Immune response; Solid tumour; Therapy resistance