Early therapy evaluation of combined anti-death receptor 5 antibody and gemcitabine in orthotopic pancreatic tumor xenografts by diffusion-weighted magnetic resonance imaging.
Early therapy evaluation of combined anti-death receptor 5 antibody and gemcitabine in orthotopic pancreatic tumor xenografts by diffusion-weighted magnetic resonance imaging.
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DOI：
10.1158/0008-5472.can-08-1771
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Zinn KR
中科院分区：
文献类型：
--
作者：
Kim H;Morgan DE;Buchsbaum DJ;Zeng H;Grizzle WE;Warram JM;Stockard CR;McNally LR;Long JW;Sellers JC;Forero A;Zinn KR
使用弥散加权磁共振成像 (DWI) 在原位胰腺肿瘤模型中测量抗 DR5 抗体 (TRA-8) 联合吉西他滨的早期治疗效果。第 1-4 组 SCID 小鼠（n=5-7/组），原位植入荧光素酶阳性人胰腺肿瘤（MIA PaCa-2），随后（4-5 周后）在第 0 天分别注射盐水（对照）、吉西他滨（120mg/kg）、TRA-8（200μg）或 TRA-8 联合吉西他滨。DWI、解剖 MRI 和治疗后第0、1、2和3天进行生物发光成像。成像后第3天随机收集每组的三个肿瘤，并进行TUNEL染色以量化凋亡细胞。开始治疗后仅1天，第3组（TRA-8）和第4组（TRA-8/Gem）肿瘤区域表观扩散系数（ADC）的变化分别为21±9%（平均值±SE）和27±3%，显着高于（p <0.05）第1组（-1±5%）和第2组（-2±4%）。此时各组的肿瘤体积没有统计学差异。第 2-4 组的平均 ADC 值在 3 天内逐渐增加，这与肿瘤体积消退和生物发光信号减少同时发生。第1-4组肿瘤的凋亡细胞密度分别为0.7±0.4%、0.6±0.2%、3.1±0.9%和4.7±1.0%，与第1天的ADC变化呈线性正比。此外，ADC变化与先前报道的用相同药物和剂量治疗的动物的平均存活时间高度相关。本研究支持临床上使用DWI对胰腺肿瘤患者进行药物疗效的早期评估。
Early therapeutic efficacy of anti-DR5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1–4 of SCID mice (n=5–7/group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4–5 weeks thereafter) injected with saline (control), gemcitabine (120mg/kg), TRA-8 (200μg), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomical MRI, and bioluminescence imaging were performed on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and TUNEL staining was performed to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for groups 3 (TRA-8) and 4 (TRA-8/Gem) were 21±9% (mean±SE) and 27±3%, respectively, significantly higher (p <0.05) than those of groups 1 (−1±5%) and 2 (−2±4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2–4 gradually increased over 3 days, which were concurrent with tumor-volume regressions and bioluminescence-signal decreases. Apoptotic-cell densities of tumors in groups 1–4 were 0.7±0.4%, 0.6±0.2%, 3.1±0.9%, and 4.7±1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy.