title: Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil.
abstract: OBJECTIVE
  Our research group previously identified specific endogenous platinum-induced fatty acids (PIFAs) that, in picomolar quantities, activate splenic macrophages leading to resistance to chemotherapy in mouse models. Fish oil was shown to contain the PIFA 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) and when administered to mice neutralized chemotherapy activity.
  
  
  OBJECTIVE
  Because patients with cancer frequently use fish oil supplements, we set out to determine exposure to 16:4(n-3) after intake of fish or fish oil.
  
  
  METHODS
  (1) In November 2011, 400 patients with cancer undergoing treatment at the University Medical Center Utrecht were surveyed to determine their use of fish oil supplements; 118 patients responded to the questionnaire (30%); (2) pharmacokinetic analysis of the 16:4(n-3) content of 6 fish oils and 4 fishes was carried out; (3) from April through November 2012, a healthy volunteer study was performed to determine 16:4(n-3) plasma levels after intake of 3 different brands of fish oil or 4 different fish species. Thirty healthy volunteers were randomly selected for the fish oil study; 20 were randomly selected for the fish study. These studies were supported by preclinical tumor experiments in mice to determine chemoresistance conducted between September 2011 and December 2012.
  
  
  METHODS
  (1) Rate of use of fish oil supplements among patients undergoing cancer treatment at our institution; (2) levels of 16:4(n-3) present in 3 brands of fish oil and 4 species of fish; and (3) plasma levels of 16:4(n-3) present in healthy volunteers after consuming fish oil or fish.
  
  
  RESULTS
  Eleven percent of respondents reported using omega-3 supplements. All fish oils tested contained relevant amounts of 16:4(n-3), from 0.2 to 5.7 µM. Mouse experiments showed that addition of 1 µL of fish oil to cisplatin was sufficient to induce chemoresistance, treatment having no impact on the growth rate of tumors compared with vehicle-treated controls (estimated tumor volume difference, 44.1 mm3; P > .99). When the recommended daily amount of 10 mL of fish oil was administered to healthy volunteers, rises in plasma 16:4(n-3) levels were observed, reaching up to 20 times the baseline levels. Herring and mackerel contained high levels of 16:4(n-3) in contrast to salmon and tuna. Consumption of fish with high levels of 16:4(n-3) also resulted in elevated plasma levels of 16:4(n-3).
  
  
  CONCLUSIONS
  All tested fish oils and herring and mackerel fishes contained relevant levels of fatty acid 16:4(n-3), a fatty acid with chemotherapy-negating effects in preclinical models. After ingestion of these fish oils or fishes, 16:4(n-3) was rapidly taken up in the plasma of human volunteers. Until further data become available, fish oil and fish containing high levels of 16:4(n-3) may best be avoided on the days surrounding chemotherapy.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, the Netherlands.
authors.forename: Laura G M
authors.initials: LG
authors.lastname: Daenen
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, the Netherlands.
authors.forename: Geert A
authors.initials: GA
authors.lastname: Cirkel
authors.affiliation: Department of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Houthuijzen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Gerrits
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, the Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Oosterom
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, the Netherlands.
authors.forename: Jeanine M L
authors.initials: JM
authors.lastname: Roodhart
authors.affiliation: Department of Biometrics, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.affiliation: National Research Institute of Fisheries Science Kanazawaku, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, the Netherlands.
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven-Duif
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, the Netherlands2Department of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000046:Academic Medical Centers; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005227:Fatty Acids / Q000097:blood*; D005395:Fish Oils / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005399:Fishes; D018565:Food-Drug Interactions; D019538:Health Care Surveys; D006801:Humans; D000077146:Irinotecan; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009426:Netherlands; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017747:Seafood; D011795:Surveys and Questionnaires; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D005227:Fatty Acids; D005395:Fish Oils; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin