title: Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy.
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-.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Renier
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Do
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Reyna-Neyra
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Deshka
authors.initials: D
authors.lastname: Foster
authors.affiliation: Department of Radiology and Molecular Imaging Program at Stanford, Stanford, CA, USA.|Molecular Functional Imaging Laboratory, ACTREC Tata Memorial Centre, Navi Mumbai, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: De
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Stefanie S
authors.initials: SS
authors.lastname: Jeffrey
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tse
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Carrasco
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Wapnir
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008819:Mice, Nude; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000099209:Sodium-Iodide Symporters
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D007457:Iodine Radioisotopes; D027981:Symporters; D000093542:Gemcitabine; D000099209:Sodium-Iodide Symporters
keywords: breast cancer brain metastases (BCBMs); radioiodide therapy; sodium/iodide symporter (NIS)