Elias Immanuel Ordell Sundelin1, Nidal Al-Suliman2, Pernille Vahl3, Mikkel Vendelbo4, Ole Lajord Munk4, Steen Jakobsen4, Steen Bønløkke Pedersen5,6, Jørgen Frøkiær4, Lars C Gormsen4, Niels Jessen7,8,9,10,11. 1. Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. 2. Department of Surgery, Aarhus University Hospital, Aarhus, Denmark. 3. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. 6. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark. 7. Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. niels.jessen@biomed.au.dk. 8. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark. niels.jessen@biomed.au.dk. 9. Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark. niels.jessen@biomed.au.dk. 10. Department of Biomedicine, Aarhus University, Aarhus, Denmark. niels.jessen@biomed.au.dk. 11. Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3 2.sal, 8200, Aarhus N, Denmark. niels.jessen@biomed.au.dk.
Abstract
PURPOSE: Epidemiological studies and randomized clinical trials suggest that the antidiabetic drug, metformin, may have anti-neoplastic effects. The mechanism that mediates these beneficial effects has been suggested to involve direct action on cancer cells, but this will require distribution of metformin in tumor tissue. The present study was designed to investigate metformin distribution in vivo in breast and liver tissue in breast cancer patients. METHODS: Seven patients recently diagnosed with ductal carcinoma were recruited. Using PET/CT, tissue distribution of metformin was determined in vivo for 90 min after injection of a carbon-11-labeled metformin tracer. After surgery, tumor tissue was investigated for gene expression levels of metformin transporter proteins. RESULTS: Tumor tissue displayed a distinct uptake of metformin compared to normal breast tissue AUC0-90 min (75.4 ± 5.5 vs 42.3 ± 6.3) g/ml*min (p = 0.01). Maximal concentration in tumor was at 1 min where it reached approximately 30% of the activity in the liver. The metformin transporter protein with the highest gene expression in tumor tissue was multidrug and toxin extrusion 1 (MATE 1) followed by plasma membrane monoamine transporter (PMAT). CONCLUSION: This study confirms that metformin is transported into tumor tissue in women with breast cancer. This finding support that metformin may have direct anti-neoplastic effects on tumor cells in breast cancer patients. However, distribution of metformin in tumor tissue is markedly lower than in liver, an established metformin target tissue.
PURPOSE: Epidemiological studies and randomized clinical trials suggest that the antidiabetic drug, metformin, may have anti-neoplastic effects. The mechanism that mediates these beneficial effects has been suggested to involve direct action on cancer cells, but this will require distribution of metformin in tumor tissue. The present study was designed to investigate metformin distribution in vivo in breast and liver tissue in breast cancerpatients. METHODS: Seven patients recently diagnosed with ductal carcinoma were recruited. Using PET/CT, tissue distribution of metformin was determined in vivo for 90 min after injection of a carbon-11-labeled metformin tracer. After surgery, tumor tissue was investigated for gene expression levels of metformin transporter proteins. RESULTS:Tumor tissue displayed a distinct uptake of metformin compared to normal breast tissue AUC0-90 min (75.4 ± 5.5 vs 42.3 ± 6.3) g/ml*min (p = 0.01). Maximal concentration in tumor was at 1 min where it reached approximately 30% of the activity in the liver. The metformin transporter protein with the highest gene expression in tumor tissue was multidrug and toxin extrusion 1 (MATE 1) followed by plasma membrane monoamine transporter (PMAT). CONCLUSION: This study confirms that metformin is transported into tumor tissue in women with breast cancer. This finding support that metformin may have direct anti-neoplastic effects on tumor cells in breast cancerpatients. However, distribution of metformin in tumor tissue is markedly lower than in liver, an established metformin target tissue.
Authors: Sirwan Hadad; Takayuki Iwamoto; Lee Jordan; Colin Purdie; Susan Bray; Lee Baker; Gera Jellema; Steve Deharo; D Grahame Hardie; Lajos Pusztai; Stacy Moulder-Thompson; John A Dewar; Alastair M Thompson Journal: Breast Cancer Res Treat Date: 2011-06-08 Impact factor: 4.872
Authors: Saroj Niraula; Ryan J O Dowling; Marguerite Ennis; Martin C Chang; Susan J Done; Nicky Hood; Jaime Escallon; Wey Liang Leong; David R McCready; Michael Reedijk; Vuk Stambolic; Pamela J Goodwin Journal: Breast Cancer Res Treat Date: 2012-08-30 Impact factor: 4.872
Authors: Eio Sundelin; L C Gormsen; J B Jensen; M H Vendelbo; S Jakobsen; O L Munk; Mmh Christensen; K Brøsen; J Frøkiaer; N Jessen Journal: Clin Pharmacol Ther Date: 2017-06-01 Impact factor: 6.875
Authors: Garry G Graham; Jeroen Punt; Manit Arora; Richard O Day; Matthew P Doogue; Janna K Duong; Timothy J Furlong; Jerry R Greenfield; Louise C Greenup; Carl M Kirkpatrick; John E Ray; Peter Timmins; Kenneth M Williams Journal: Clin Pharmacokinet Date: 2011-02 Impact factor: 6.447
Authors: Bolin Liu; Zeying Fan; Susan M Edgerton; Xin-Sheng Deng; Irina N Alimova; Stuart E Lind; Ann D Thor Journal: Cell Cycle Date: 2009-07-21 Impact factor: 4.534
Authors: Lars C Gormsen; Elias Immanuel Sundelin; Jonas Brorson Jensen; Mikkel Holm Vendelbo; Steen Jakobsen; Ole Lajord Munk; Mette Marie Hougaard Christensen; Kim Brøsen; Jørgen Frøkiær; Niels Jessen Journal: J Nucl Med Date: 2016-07-28 Impact factor: 10.057