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Original Investigation |

Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil

Laura G. M. Daenen, MD, PhD1; Geert A. Cirkel, MD1; Julia M. Houthuijzen, MSc2; Johan Gerrits, BSc3; Ilse Oosterom, MSc1; Jeanine M. L. Roodhart, MD, PhD1; Harm van Tinteren, PhD4; Kenji Ishihara, PhD5; Alwin D. R. Huitema, PharmD6; Nanda M. Verhoeven-Duif, PhD3; Emile E. Voest, MD, PhD1,2
[+] Author Affiliations
1Department of Medical Oncology, University Medical Center Utrecht, the Netherlands
2Department of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
3Department of Medical Genetics, University Medical Center Utrecht, the Netherlands
4Department of Biometrics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
5National Research Institute of Fisheries Science Kanazawaku, Yokohama, Japan
6Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands
JAMA Oncol. 2015;1(3):350-358. doi:10.1001/jamaoncol.2015.0388.
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Importance  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.

Design, Setting, and Participants  (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.

Main Outcomes and Measures  (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 and Relevance  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.

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Figure 1.
Fish Oil Effects on Cisplatin Activity in Mice

A, Dose of 2.5 pmol of 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) was administered to tumor-bearing mice alone or combined with cisplatin; all depicted tumor volumes were measured on day 4 after therapy. B, Fish oil A (100 µL) and cisplatin were administered to tumor-bearing mice. Tumor growth was monitored; volumes were log transformed; and differences between the intervention groups were calculated using repeated measurement analyses; error bars indicate standard error of the mean (SEM). C, Fish oil A (100 µL), oxaliplatin, and irinotecan were administered to tumor-bearing mice; all depicted tumor volumes were measured on day 6 after therapy. D, Tumor-bearing mice were treated with cisplatin, pure fish oil A (100 µL), or fish oil A diluted 1:10, 1:100, or 1:1000 in sunflower oil (SFO). Fish oil A (100 µL) and the combination of SFO (100 µL) and cisplatin were administered as controls; all depicted tumor volumes were measured on day 4 after therapy. All P values represent the comparison with vehicle unless otherwise indicated by group-spanning brackets. All whiskers and box plot points represent the distribution of the parameters at fixed times.

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Figure 2.
Effects of Fish Oil Ingestion on Plasma Levels of 16:4(n-3) (Hexadeca-4,7,10,13-tetraenoic Acid) in Healthy Human Volunteers

Three fish oils were administered to 6 volunteers each in either 10- or 50-mL doses; each graph line represents 1 volunteer. Calculated quantities of ingested 16:4(n-3) are shown in parentheses in the panel labels. The average area under the curve (AUC) (0-8 hours) was calculated for each fish oil; whiskers and box plots represent the distribution of the parameters at fixed times.

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Figure 3.
Metabolization in Mice of Other Fatty Acids in Fish Oil to 16:4(n-3) (Hexadeca-4,7,10,13-tetraenoic Acid)

A, Undifferentiated fish oil A administered to mice; plasma withdrawn and evaluated for 16:4(n-3) levels. B, Dose of 543 pmol of 16:4(n-3) administered to mice; plasma withdrawn and evaluated for 16:4(n-3) levels. C, Dose of 69 µmol of EPA administered to mice; plasma withdrawn and evaluated for 16:4(n-3) levels. D, Dose of 69 µmol of EPA and cisplatin administered to tumor-bearing mice and tumor volume plotted; whiskers and box plots represent the distribution of the parameters at fixed times (P value represents comparison with vehicle). E, Dose of 690 nmol of EPA and cisplatin administered to tumor-bearing mice; tumor growth monitored. Error bars in panels A, B, C, and E represent standard error of the mean (SEM).

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Figure 4.
Effects of Consumption of Fish Containing 16:4(n-3) (Hexadeca-4,7,10,13-tetraenoic Acid) on Plasma Levels of 16:4(n-3) in Healthy Human Volunteers

As can be seen by the quantities of 16:4(n-3) contained in the ingested fish portions (shown in parentheses in the panel labels), mackerel and herring contained high levels, and salmon and tuna contained low levels. Each fish portion of 100 g was ingested by 5 volunteers; plasma samples were then taken, evaluated, and plotted. In the box plot, the average area under the curve (AUC) (0-24 hours) was calculated; whiskers and box plots represent the distribution of the parameters at fixed times.

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