Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, VA Medical Center, Oklahoma City, Oklahoma.
Mol Carcinog. 2019 Oct;58(10):1908-1918. doi: 10.1002/mc.23084. Epub 2019 Jul 16.
Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ-26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in Kras mice. After dose selection using wild-type mice, six-week-old p48 -LSL-Kras (22-24 per group) genetically engineered mice (GEM) were fed AIN-76A diets containing 0, 250, or 500 ppm JNJ-26070109 or YF-476 for 38 weeks. At termination, pancreata were collected, weighed, and evaluated for PanINs and PDAC. Results demonstrated that control-diet-fed mice showed 69% (males) and 33% (females) incidence of PDAC. Administration of low and high dose JNJ-26070109 inhibited the incidence of PDAC by 88% and 71% (P < .004) in male mice and by 100% and 24% (P > .05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P < .02) and 69% (P < .02) in male mice and by 45% and 33% (P > .05) in female mice, respectively. Further, transcriptome analysis showed downregulation of Cldn1, Sstr1, Apod, Gkn1, Siglech, Cyp2c44, Bnc1, Fmo2, 623169, Kcne4, Slc27a6, Cma1, Rho GTPase activating protein 18, and Gpr85 genes in JNJ-26070109-treated mice compared with untreated mice. YF476-treated mouse pancreas showed downregulation of Riks, Zpbp, Ntf3, Lrrn4, Aass, Skint3, Kcnb1, Dgkb, Ddx60, and Aspn gene expressions compared with untreated mouse pancreas. Overall, JNJ-26070109 showed better chemopreventive efficacy than YF476. However, caution is recommended when selecting doses, as the agents appeared to exhibit gender-specific effects.
通过胆囊收缩素-2 受体 (CCK2R) 及其下游分子介导的胃泌素信号在胰腺癌中发生改变。系统测试了 CCK2R 拮抗剂 YF476（netazepide）和 JNJ-26070109 对 Kras 小鼠胰腺上皮内瘤变 (PanIN) 进展为胰腺导管腺癌 (PDAC) 的影响。在使用野生型小鼠进行剂量选择后，用含有 0、250 或 500ppm JNJ-26070109 或 YF-476 的 AIN-76A 饮食喂养六周龄 p48 -LSL-Kras（每组 22-24 只）基因工程小鼠 (GEM) 38 周。在终末时，收集胰腺，称重，并评估 PanIN 和 PDAC。结果表明，对照饮食喂养的小鼠中雄性 PDAC 的发生率为 69%，雌性为 33%。低剂量和高剂量 JNJ-26070109 分别使雄性小鼠的 PDAC 发生率降低 88%和 71%（P<.004），雌性小鼠分别降低 100%和 24%（P>.05）。低剂量和高剂量 YF476 分别使雄性小鼠的 PDAC 发生率降低 74%（P<.02）和 69%（P<.02），雌性小鼠分别降低 45%和 33%（P>.05）。此外，转录组分析表明，与未处理的小鼠相比，JNJ-26070109 处理的小鼠的 Cldn1、Sstr1、Apod、Gkn1、Siglech、Cyp2c44、Bnc1、Fmo2、623169、Kcne4、Slc27a6、Cma1、Rho GTPase 激活蛋白 18 和 Gpr85 基因表达下调。与未处理的小鼠胰腺相比，YF476 处理的小鼠胰腺中的 Riks、Zpbp、Ntf3、Lrrn4、Aass、Skint3、Kcnb1、Dgkb、Ddx60 和 Aspn 基因表达下调。总体而言，JNJ-26070109 的化学预防效果优于 YF476。然而，在选择剂量时应谨慎，因为这些药物似乎表现出性别特异性作用。
