Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Gut. 2018 Jul;67(7):1290-1298. doi: 10.1136/gutjnl-2017-313942. Epub 2017 Nov 9.
The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc mice with known tumour-bearing status at treatment initiation.
Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both.
The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of and significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1).
The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.
受试者对预防干预的反应存在异质性。本研究的目的是确定化学预防剂在无肿瘤荷瘤动物与结直肠肿瘤荷瘤动物中的疗效是否存在差异。在开始治疗时，已知具有肿瘤携带状态的 Apc 小鼠给予舒林酸和/或阿托伐他汀。
雄性小鼠（6-8 周龄）行结肠镜检查，并给予对照饲料或含舒林酸（300ppm）、阿托伐他汀（100ppm）或舒林酸/阿托伐他汀的饲料。治疗 14 周（组织病理学）或 7 天（基因表达）后收集小鼠组织。用舒林酸、阿托伐他汀或两者处理 SW480 结肠癌细胞，进行细胞周期分析。
基线时存在肿瘤的未处理小鼠的结直肠腺瘤多发性是基线时无肿瘤小鼠的 3.6 倍（P=0.002）。阿托伐他汀完全抑制了基线时无肿瘤小鼠微腺瘤的形成（P=0.018），并改变了与干细胞/祖细胞相关的基因表达。与未处理的荷瘤小鼠相比，荷瘤小鼠用舒林酸/阿托伐他汀治疗导致结直肠腺瘤多发性降低 43%（P=0.049）。舒林酸/阿托伐他汀显著增加 和 的表达，表明细胞周期调节在肿瘤抑制中的重要性。用舒林酸/阿托伐他汀处理 SW480 细胞导致细胞周期停滞（G0/G1）。
动物在治疗开始时的肿瘤状态决定了对治疗干预的反应。阿托伐他汀消除了无肿瘤小鼠的微腺瘤。在荷瘤小鼠中观察到的 Sul/Atorva 肿瘤抑制作用大于每种药物单独使用的作用。
