Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos.
Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos.
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发表时间：
2000-04
期刊：
影响因子：
11.2
通讯作者：
R. Jacoby;C. Cole;K. Tutsch;M. A. Newton;G. Kelloff;E. Hawk;R. Lubet
中科院分区：
文献类型：
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作者：
R. Jacoby;C. Cole;K. Tutsch;M. A. Newton;G. Kelloff;E. Hawk;R. Lubet
基因敲除或药物抑制环氧合酶-2可减少家族性腺瘤性息肉病小鼠模型中腺瘤的数量和大小。人类流行病学和临床研究表明，抑制考克斯-1和考克斯-2酶的整个类别的非甾体抗炎药（NSAID）是有前途的结肠癌化学预防剂。我们使用Apc突变Min小鼠模型来测试可能以最小毒性最大化预防益处的药剂组合，因为它们通过不同的机制起作用。Min小鼠（n = 144）暴露于低剂量的非选择性考克斯抑制剂吡罗昔康和鸟氨酸脱羧酶（ODC）抑制剂二氟甲基鸟氨酸（DFMO），从它们断奶时开始，并在整个实验期间持续。吡罗昔康在12，25和50 ppm的饮食引起剂量依赖性的减少肿瘤的数量在小肠的中部和远端部分。这种肿瘤多样性的减少与那些确实生长出来的肿瘤的大小显著减少有关。相比之下，吡罗昔康单独给药均未降低肠近端部分（十二指肠）的肿瘤多样性。暴露于DFMO（0.5%或1.0%水溶液）导致小肠中段和远端肿瘤多样性呈剂量依赖性降低。然而，这种减少的多样性与肿瘤大小的显著减少无关。吡罗昔康加DFMO联合治疗小鼠比单独使用任一种药物有效得多，并导致大量小鼠完全没有任何肠腺瘤（P < 0.001），而对照Min小鼠的发病率为100%，多样性高。除了在减少肿瘤数量方面的显著效果外，用联合药物治疗的小鼠中的少量残留肿瘤的大小明显小于对照Min小鼠产生的肿瘤。这些实验表明，选择性考克斯-2抑制与ODC抑制相结合是一种非常有前途的结肠癌预防方法。这些考克斯-2和ODC抑制剂药物在断奶后给予小鼠时所用剂量下没有明显毒性。然而，当在子宫内开始给药时，不再观察到我们在未给药对照窝仔中常规获得的孟德尔预期子代比1：1。吡罗昔康和/或DFMO处理的妊娠母鼠的Apc（min）/+子代数量减少，其与Apc+/+子代的比例降至约0.28：1。因此，这些药剂对具有APC基因纯合突变的腺瘤有效，并且还选择对APC基因中具有杂合突变的胎儿有效。
Genetic knockout or pharmacological inhibition of cyclooxygenase-2 decreases the number and size of adenomas in mouse models of familial adenomatous polyposis. Epidemiological and clinical studies in humans indicate that the entire class of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both COX-1 and COX-2 enzymes are promising colon cancer chemopreventive agents. We used the Apc mutant Min mouse model to test combinations of agents that might maximize preventive benefit with minimal toxicity because they act via different mechanisms. Min mice (n = 144) were exposed to low doses of the nonselective COX inhibitor piroxicam and the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO), beginning at the time they were weaned and continuing throughout the duration of the experiment. Piroxicam at 12, 25, and 50 ppm in the diet caused dose-dependent decreases in the number of tumors in the middle and distal portions of the small intestine. This decrease in tumor multiplicity was associated with a striking decrease in the size of those tumors that did grow out. In contrast, none of the doses of piroxicam alone decreased tumor multiplicity in the proximal portion of the intestine (duodenum). Exposure to DFMO (0.5 or 1.0% in water) caused a dose-dependent decrease in tumor multiplicity in the middle and distal portions of the small intestine. However, this decreased multiplicity was not associated with a striking decrease in the size of the tumors. Combined treatment of mice with piroxicam plus DFMO was much more effective than either agent alone and resulted in a significant number of mice totally free of any intestinal adenomas (P < 0.001), in contrast to the 100% incidence and high multiplicity in control Min mice. In addition to this profound effectiveness in reducing tumor number, the few residual tumors in mice treated with the combined drugs were markedly smaller in size than tumors that arose from control Min mice. These experiments suggest that selective COX-2 inhibition combined with ODC inhibition is a very promising approach for colon cancer prevention. These COX-2 and ODC inhibitor drugs were not overtly toxic at the doses used when administered to mice after weaning. However, when treatment was begun in utero, the Mendelian expected progeny ratio of 1:1 that we routinely obtained in untreated control litters was no longer observed. Apc(min)/+ progeny of pregnant dams treated with piroxicam and/or DFMO were reduced in number and their ratio to Apc+/+ progeny was decreased to approximately 0.28:1. Thus, these agents are effective against adenomas that have homozygous mutation of the APC gene and also select against fetuses bearing a heterozygous mutation in the APC gene.