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Oncotarget. 2016 Aug 23;7(34):54811-54824. doi: 10.18632/oncotarget.10238.

Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy.

Author information

1
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
3
Department of Radiology and Molecular Imaging Program at Stanford, Stanford, CA, USA.
4
Molecular Functional Imaging Laboratory, ACTREC Tata Memorial Centre, Navi Mumbai, India.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.

Abstract

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-.

KEYWORDS:

breast cancer brain metastases (BCBMs); radioiodide therapy; sodium/iodide symporter (NIS)

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