Objective 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+/Min-FCCC mice with known tumour-bearing status at treatment initiation. Design 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. Results 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 Hoxb13 and Rprm 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). Conclusions 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.

中文翻译：

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舒林酸和阿托伐他汀对有或无结直肠腺瘤的 Apc+/Min-FCCC 小鼠的差异预防活性

目的 受试者对预防干预的反应是异质的。本研究的目的是确定化学预防剂在非肿瘤动物与结直肠肿瘤动物中的功效是否不同。在治疗开始时，将舒林酸和/或阿托伐他汀给予具有已知荷瘤状态的 Apc+/Min-FCCC 小鼠。设计 雄性小鼠（6-8 周龄）接受结肠镜检查并接受对照饲料或含舒林酸（300 ppm）、阿托伐他汀（100 ppm）或舒林酸/阿托伐他汀的饲料。从治疗 14 周（组织病理学）或 7 天（基因表达）的小鼠中收集组织。对用舒林酸、阿托伐他汀或两者处理的 SW480 结肠癌细胞进行细胞周期分析。结果 在基线时，未经治疗的携带肿瘤的小鼠中结直肠腺瘤的多样性为 3。比基线时无肿瘤的小鼠高 6 倍 (P=0.002)。阿托伐他汀完全抑制了基线时无肿瘤的小鼠微腺瘤的形成（P=0.018），并改变了与干细胞/祖细胞相关的基因的表达。与未治疗的荷瘤小鼠相比，用舒林酸/阿托伐他汀治疗荷瘤小鼠导致结直肠腺瘤的多样性降低 43% (P=0.049)。舒林酸/阿托伐他汀显着增加了 Hoxb13 和 Rprm 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)。结论 治疗开始时动物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。