Oncotarget

Research Papers:

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

Corinne Renier, John Do, Andrea Reyna-Neyra, Deshka Foster, Abhijit De, Hannes Vogel, Stefanie S. Jeffrey, Victor Tse, Nancy Carrasco and Irene Wapnir _

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Oncotarget. 2016; 7:54811-54824. https://doi.org/10.18632/oncotarget.10238

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Abstract

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

Correspondence to:

Irene Wapnir, email: wapnir@stanford.edu

Keywords: sodium/iodide symporter (NIS), radioiodide therapy, breast cancer brain metastases (BCBMs)

Received: August 26, 2015    Accepted: May 19, 2016    Published: June 23, 2016

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.


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