Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy
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Corinne Renier1, John Do1,*, Andrea Reyna-Neyra2,*, Deshka Foster1, Abhijit De3,4, Hannes Vogel5, Stefanie S. Jeffrey1, Victor Tse6, Nancy Carrasco2, Irene Wapnir1
1Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
2Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
3Department of Radiology and Molecular Imaging Program at Stanford, Stanford, CA, USA
4Molecular Functional Imaging Laboratory, ACTREC Tata Memorial Centre, Navi Mumbai, India
5Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
6Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
*These authors have contributed equally to this work
Irene Wapnir, email: [email protected]
Keywords: sodium/iodide symporter (NIS), radioiodide therapy, breast cancer brain metastases (BCBMs)
Received: August 26, 2015 Accepted: May 19, 2016 Published: June 23, 2016
Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I− symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I−). We show impressive enhancement of tumor response by combining131I− with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I−/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg×4); 131I− (1mCi or 2×0.5 mCi 7 days apart); and 131I−/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I−-treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I−/ GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I− delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I− caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I−.
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