Ritland S R, Gendler S J
Mayo Clinic Arizona, Department of Biochemistry and Molecular Biology, Scottsdale 85259, USA.
Carcinogenesis. 1999 Jan;20(1):51-8. doi: 10.1093/carcin/20.1.51.
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 ApcMin 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, C57BI/ 6J-ApcMin mice were fed either the control diet (AIN-93G) or AIN-93G plus 200 p.p.m. piroxicam. Tumor multiplicity was significantly reduced in ApcMin 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 ApcMin 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 ApcMin 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 Apc inactivation are not likely to account for the observed difference in chemoresistance.
以往的癌症化学预防研究表明，非甾体抗炎药（NSAIDs）可有效抑制肠道肿瘤的发生。为进一步探讨这一问题，我们在ApcMin小鼠中使用吡罗昔康进行了交叉化学预防研究，以评估NSAIDs介导的肿瘤消退动力学、遗传背景的影响以及化学预防耐药的发生率。从断奶时开始，给C57BI/6J-ApcMin小鼠喂食对照饮食（AIN-93G）或AIN-93G加200 ppm吡罗昔康。在喂食200 ppm吡罗昔康直至100或200日龄的ApcMin小鼠中，肿瘤多发性显著降低（肿瘤数量分别减少94.4%和95.7%；与AIN-93G对照组相比，P<0.001）。当吡罗昔康给药推迟至100日龄且小鼠在200日龄时处死时，肿瘤多发性降低了96.2%（与对照组相比，P<0.001）。或者，当吡罗昔康给药在100日龄时暂停且小鼠在200日龄时处死时，肿瘤多发性降低了68.0%（与对照组相比，P<0.001）。对已有肿瘤的ApcMin动物进行短期药物治疗期研究发现，吡罗昔康诱导的肿瘤消退动力学很快：用200 ppm吡罗昔康治疗1周后，肿瘤多发性降低>90%。吡罗昔康治疗小鼠中残留肿瘤的分布表明十二指肠和结肠的肿瘤对化学抑制相对耐药。用200 ppm吡罗昔康治疗种间杂交ApcMin小鼠表明，化学抑制存在品系相关效应，提示存在调节NSAIDs化学敏感性的遗传因素。最后，全基因组等位基因缺失研究表明，F1小鼠的NSAIDs耐药肿瘤中几乎没有独特的染色体缺失，这意味着Apc失活继发的功能丧失突变不太可能解释观察到的化学耐药差异。
