在小鼠前列腺癌同基因模型中建立镥 - PSMA - 617放射性配体疗法。
Establishing Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer.
作者信息
Fendler Wolfgang P, Stuparu Andreea D, Evans-Axelsson Susan, Lückerath Katharina, Wei Liu, Kim Woosuk, Poddar Soumya, Said Jonathan, Radu Caius G, Eiber Matthias, Czernin Johannes, Slavik Roger, Herrmann Ken
机构信息
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.
出版信息
J Nucl Med. 2017 Nov;58(11):1786-1792. doi: 10.2967/jnumed.117.193359. Epub 2017 May 25.
Clinical Lu-PSMA-617 radioligand therapy (RLT) is applied in advanced-stage prostate cancer. However, to the best of our knowledge murine models to study the biologic effects of various activity levels have not been established. The aim of this study was to optimize specific and total activity for Lu-PSMA-617 RLT in a syngeneic model of murine prostate cancer. Murine-reconstituted, oncogene-driven prostate cancer cells (0.1 × 10) (RM1), transduced to express human prostate-specific membrane antigen (PSMA), were injected into the left flank of C57Bl6 immunocompetent mice. RLT was performed by administering a single tail vein injection of Lu-PSMA-617 at different formulations for specific (60 MBq at high, 62 MBq/nmol; intermediate, 31 MBq/nmol; or low 15 MBq/nmol specific activity) or total activity (30, 60, or 120 MBq). Organ distribution was determined by ex vivo γ-counter measurement. DNA double-strand breaks were measured using anti-gamma-H2A.X (phospho S139) immunohistochemistry. Efficacy was assessed by serial CT tumor volumetry and F-FDG PET metabolic volume. Toxicity was evaluated 4 wk after the start of RLT. Mean tumor-to-kidney ratios ± SEM were 19 ± 5, 10 ± 5, and 2 ± 0 for high, intermediate, and low (each = 3) specific activity, respectively. Four of 6 (67%) mice treated with intermediate or high specific activity and none of 6 (0%) mice treated with low specific activity or formulation demonstrated significant DNA double-strand breaks (≥5% γ-H2A.X-positive cells). High when compared with intermediate or low specific activity resulted in a lower mean ± SEM tumor load by histopathology (vital tissue, 4 ± 2 vs. 8 ± 3 mm; = 3 vs. 6), day-4 F-FDG PET (metabolic volume, 87 ± 23 vs. 118 ± 14 mm; = 6 vs. 12), and day-7 CT (volume, 323 ± 122 vs. 590 ± 46 mm; = 3 vs. 6; = 0.039). Lu-PSMA-617 (120 MBq) with high specific activity induced superior tumor growth inhibition ( = 0.021, = 5/group) without subacute hematologic toxicity ( = 3/group). Lu-PSMA-617 (120 MBq) and high specific activity resulted in the highest efficacy in a syngeneic model of murine prostate cancer. The model will be useful for studying the effects of PSMA-directed RLT combined with potentially synergistic pharmacologic approaches.
临床Lu-PSMA-617放射性配体疗法（RLT）应用于晚期前列腺癌。然而，据我们所知，尚未建立用于研究不同活性水平生物学效应的小鼠模型。本研究的目的是在小鼠前列腺癌同基因模型中优化Lu-PSMA-617 RLT的比活度和总活度。将经转导以表达人前列腺特异性膜抗原（PSMA）的小鼠重组、癌基因驱动的前列腺癌细胞（0.1×10）（RM1）注射到C57Bl6免疫活性小鼠的左侧腹。通过经尾静脉单次注射不同配方的Lu-PSMA-617进行RLT，具体配方为不同的比活度（高比活度60 MBq，62 MBq/nmol；中比活度31 MBq/nmol；或低比活度15 MBq/nmol）或总活度（30、60或120 MBq）。通过体外γ计数器测量确定器官分布。使用抗γ-H2A.X（磷酸化S139）免疫组织化学测量DNA双链断裂。通过连续CT肿瘤体积测量和F-FDG PET代谢体积评估疗效。在RLT开始后4周评估毒性。高、中、低（每组n = 3）比活度的平均肿瘤与肾脏比值±SEM分别为19±5、10±5和2±0。接受中比活度或高比活度治疗的6只小鼠中有4只（67%）出现显著的DNA双链断裂（≥5%γ-H2A.X阳性细胞），而接受低比活度或配方治疗的6只小鼠中无一例（0%）出现显著的DNA双链断裂。与中比活度或低比活度相比，高比活度通过组织病理学（存活组织，4±2 vs. 8±3 mm；n = 3 vs. 6）、第4天F-FDG PET（代谢体积，87±23 vs. 118±14 mm；n = 6 vs. 12）和第7天CT（体积，323±122 vs. 590±46 mm；n = 3 vs. 6；P = 0.039）导致平均肿瘤负荷更低。高比活度的Lu-PSMA-617（120 MBq）诱导了更好的肿瘤生长抑制（P = 0.021，每组n = 5），且无亚急性血液学毒性（每组n = 3）。在小鼠前列腺癌同基因模型中，Lu-PSMA-617（120 MBq）和高比活度产生了最高的疗效。该模型将有助于研究PSMA导向的RLT与潜在协同药理方法联合使用的效果。
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