Center for Chemoprevention and Drug Development, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Cancer Prev Res (Phila). 2010 Nov;3(11):1417-26. doi: 10.1158/1940-6207.CAPR-10-0038.
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal prognosis. Developing novel strategies to prevent or delay pancreatic cancer is currently of intense interest. The chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was evaluated against the progression of pancreatic intraepithelial neoplasms (PanIN) to PDAC in conditional LSL-Kras(G12D/+) transgenic mice. LSL-Kras(G12D/+) and p48(Cre/+) mice were bred, and offspring of activated Kras(G12D/+) were generated. Six-week-old male Kras(G12D/+) (20 per group) and C57BL/6 wild-type (12 per group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm of gefitinib for 35 weeks. At termination, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers were measured by immunohistochemistry, immunofluorescence, immunoblotting, and/or reverse transcription-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77% and 100%, respectively (P < 0.0001) when compared with control diet. Importantly, a significant inhibition of carcinoma and a dose-dependent suppression of PanINs [PanIN-1, 37-62% (P < 0.002); PanIN-2, 38-41 (P < 0.001); and PanIN-3, 7-34% (P < 0.0141)] were observed in mice treated with gefitinib. Furthermore, mice treated with 100 and 200 ppm of gefitinib exhibited 67.6% to 77.3% of the pancreas to be free from ductal lesions. Also, gefitinib reduced EGFR, proliferating cell nuclear antigen, cyclin D1, C(2)GNT, RhoA, β-catenin, p38, phospho-extracellular signal-regulated kinase, caveolin-1, and mucin and increased cyclin B1 in the pancreatic lesions/PDAC. In summary, these results show that gefitinib can prevent the progression of pancreatic cancer precursor lesions to PDAC in a preclinical model. The present study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in individuals at high risk for pancreatic cancer.
胰腺导管腺癌 (PDAC) 是最常见的胰腺恶性肿瘤，预后极差。目前，开发预防或延迟胰腺癌的新策略是当务之急。表皮生长因子受体 (EGFR) 抑制剂吉非替尼对胰腺上皮内瘤变 (PanIN) 向 PDAC 进展的化学预防作用在条件性 LSL-Kras(G12D/+)转基因小鼠中进行了评估。LSL-Kras(G12D/+) 和 p48(Cre/+) 小鼠进行繁殖，生成激活 Kras(G12D/+)的后代。6 周龄雄性 Kras(G12D/+) (每组 20 只) 和 C57BL/6 野生型 (每组 12 只) 小鼠用含有 0、100 和 200 ppm 吉非替尼的 AIN-76A 饮食喂养 35 周。在终止时，通过组织病理学评估胰腺中的 PanIN 和 PDAC，并通过免疫组织化学、免疫荧光、免疫印迹和/或逆转录-PCR 测量各种生物标志物。与对照饮食相比，饮食中 100 和 200 ppm 的吉非替尼分别显著抑制了 77%和 100%的 PDAC 发生率 (P < 0.0001)。重要的是，在吉非替尼治疗的小鼠中观察到癌的显著抑制和 PanIN 的剂量依赖性抑制[PanIN-1，37-62% (P < 0.002); PanIN-2，38-41% (P < 0.001); 和 PanIN-3，7-34% (P < 0.0141)]。此外，用 100 和 200 ppm 的吉非替尼处理的小鼠有 67.6%至 77.3%的胰腺没有导管病变。此外，吉非替尼降低了胰腺病变/PDAC 中的 EGFR、增殖细胞核抗原、细胞周期蛋白 D1、C(2)GNT、RhoA、β-连环蛋白、p38、磷酸细胞外信号调节激酶、窖蛋白-1 和粘蛋白，并增加了细胞周期蛋白 B1。综上所述，这些结果表明，吉非替尼可预防临床前模型中胰腺癌前病变向 PDAC 的进展。本研究强调了化学预防的前景以及 EGFR 抑制剂在胰腺癌高危人群中的潜在用途。
