Renier Corinne, Do John, Reyna-Neyra Andrea, Foster Deshka, De Abhijit, Vogel Hannes, Jeffrey Stefanie S, Tse Victor, Carrasco Nancy, Wapnir Irene
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
Oncotarget. 2016 Aug 23;7(34):54811-54824. doi: 10.18632/oncotarget.10238.
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-.
治疗乳腺癌脑转移瘤（BCBMs）具有挑战性。BCBMs中钠/碘同向转运体（NIS）的表达使其能够被放射性碘（131I-）选择性靶向。我们发现，将131I-与细胞毒性放射增敏剂吉西他滨（GEM）联合使用可显著增强肿瘤反应。用双顺反子连接的NIS和萤火虫荧光素酶cDNA转导的脑转移性MDA-MB-231Br细胞在裸鼠乳腺脂肪垫（MFP）中生成肿瘤和BCBMs。通过生物发光成像和NIS肿瘤表达在体内监测反应。131I-/GEM疗法比单独使用任何一种药物更有效地抑制MFP肿瘤生长。BCBMs接受以下治疗：高剂量或低剂量GEM（58或14.5mg/Kg×4）；131I-（1mCi或2×0.5mCi，间隔7天）；以及131I-/GEM疗法。到注射后第25天（PID 25），82-86%的对照和78-83%接受131I-治疗的BCBMs生长，而17%的低剂量和36%的高剂量GEM治疗的肿瘤缩小。后一组肿瘤比具有相似NIS表达（约20%的细胞）的对照小。高剂量和低剂量的131I-/GEM联合治疗分别导致89%和57%的肿瘤缩小。高剂量GEM/131I-延迟了肿瘤生长：到PID45时肿瘤大小增加了5倍（对照在PID18时）。尽管表达NIS的细胞少于25%，但GEM/131I-在NIS转导的BCBMs中导致了显著的肿瘤缩小。这种效应是协同的，并支持GEM使细胞对131I-放射增敏的假说。
