Chemoprevention of intestinal adenomas in the ApcMin mouse by piroxicam:: kinetics, strain effects and resistance to chemosuppression
Chemoprevention of intestinal adenomas in the ApcMin mouse by piroxicam:: kinetics, strain effects and resistance to chemosuppression
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DOI：
10.1093/carcin/20.1.51
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发表时间：
1999-01-01
期刊：
影响因子：
4.7
通讯作者：
Gendler, SJ
中科院分区：
文献类型：
--
作者：
Ritland, SR;Gendler, SJ
以往的癌症化学预防研究表明，非甾体抗炎药可以有效地抑制肠道肿瘤的发展。为了进一步探讨这个问题，我们在APC(Min)小鼠中使用药物吡罗昔康进行了交叉化学预防研究，以评估非甾体抗炎药介导的肿瘤消退的动力学、遗传背景的影响和化学预防耐药的发生率。从断奶时开始，C57BL/6J-APC(Min)小鼠被喂以对照饲料(AIN-93g)或AIN-93g+200p.p.m。吡罗昔康，在APC(Min)小鼠中，每天喂食200 ppm的肿瘤多样性显著降低。吡罗昔康直到100日龄或200日龄(肿瘤数量分别减少94.4%和95.7%；P<；0.001与AIN-93G对照组相比)。推迟给药至100日龄并于200日龄处死小鼠，肿瘤多样性降低96.2%(P<；0.001与对照组相比)；当停药至100日龄并于200日龄处死小鼠时，肿瘤多样性降低68.0%(P<；0.001与对照组相比)。对已建立肿瘤的APC(Min)动物的短期药物治疗表明，吡罗昔康诱导的肿瘤消退动力学迅速：200 p.p.m的治疗1周后，肿瘤多样性减少了90%。吡罗昔康。吡罗昔康治疗的小鼠中残留肿瘤的分布表明，十二指肠和结肠的肿瘤对化疗抑制相对耐受，在种间杂交APC(Min)小鼠中以200 p.p.m的剂量治疗。吡罗昔康显示存在与菌株相关的化疗抑制效应，这表明存在调节NSAID化疗敏感性的遗传元件。最后，全基因组等位基因丢失研究表明，在F1小鼠的NSAID耐药肿瘤中几乎没有独特的染色体缺失，这意味着APE失活继发的功能丧失突变不太可能解释观察到的化疗耐药性差异。
Previous cancer chemoprevention studies have demonstrated that NSAIDs can be effective in suppressing the development of intestinal tumors. To further explore this issue, we performed cross-over chemoprevention studies using the drug piroxicam in the Apc(Min) mouse to evaluate the kinetics of NSAID-mediated tumor regression, the effects of genetic background and the incidence of resistance to chemoprevention, Starting at the time of weaning, C57Bl/6J-Apc(Min) mice were fed either the control diet (AIN-93G) or AIN-93G plus 200 p.p.m. piroxicam, Tumor multiplicity was significantly reduced in Apc(Min) mice that were fed 200 p.p.m. piroxicam until 100 or 200 days of age (94.4 and 95.7% reduction in tumor number, respectively; P < 0.001 versus AIN-93G controls). When the administration of piroxicam was delayed until 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 96.2% (P < 0.001 versus controls), Alternatively, when the administration of piroxicam was suspended at 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 68.0% (P < 0.001 versus controls). Short-term drug treatment periods for Apc(Min) animals with established tumors revealed that the kinetics of piroxicam-induced tumor regression were rapid: >90% reduction in tumor multiplicity was observed after 1 week of treatment with 200 p.p.m. piroxicam. The distribution of residual tumors in piroxicam-treated mice suggests that tumors of the duodenum and colon were relatively resistant to chemosuppression, Treatment of interspecific hybrid Apc(Min) mice with 200 p.p.m. piroxicam revealed that there was a strain-related effect on chemosuppression, suggesting the existence of genetic elements which modulate NSAID chemosensitivity, Finally, whole-genome allelic loss studies showed that there were few unique chromosomal deletions in the NSAID-resistant tumors from F1 mice, implying that loss-of-function mutations secondary to Ape inactivation are not likely to account for the observed difference in chemoresistance.