Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20852, USA.
J Urol. 2010 Apr;183(4):1598-603. doi: 10.1016/j.juro.2009.12.001. Epub 2010 Feb 20.
We optimized agent testing in an in vivo bladder cancer model and determined the most sensitive, relevant protocol to test efficacy in clinical prevention trials.
Female Fischer-344 rats (Harlan) were treated with the bladder carcinogen OH-BBN (TCI America, Portland, Oregon) for 8 weeks. Rats were treated with naproxen (400 mg/kg diet), aspirin (Sigma(R)) (300 or 3,000 mg/kg diet), Iressa(R) (10 mg/kg gefitinib body weight daily) or resveratrol (1,000 mg/kg diet) using 1 of 3 protocols, including treatment beginning 1) 1 week after OH-BBN and continuing for 7 months, 2) 3 months after OH-BBN after microscopic lesions already existed and continuing for 3 months, and 3) 1 week after OH-BBN and continuing for 4 months. In protocols 1 and 2 bladder lesion weight and large tumors were primary end points, and in protocol 3 microscopic cancer was the end point.
Using protocol 1 naproxen, Iressa, resveratrol, and low and high dose aspirin altered the formation of large bladder tumors by 87% (decreased), 90% (decreased), 3% (increased), 6% (decreased) and 60% (decreased), respectively. Using protocol 2 Iressa and naproxen were also highly effective. Protocol 3 evaluation revealed that only Iressa caused a significant decrease in microscopic bladder cancers (63%).
Initiating treatment after OH-BBN or when bladder lesions already existed showed naproxen and Iressa to be effective in preventing formation of large cancers. Low dose aspirin and resveratrol were ineffective. In protocol 3, in which microscopic lesions were the end point, only Iressa was effective. Thus, an established cancer end point appears preferable. Naproxen, which has an excellent cardiovascular profile, or epidermal growth factor receptor inhibitors may be effective in an adjuvant setting.
我们优化了体内膀胱癌模型中的药物测试，并确定了最敏感、最相关的方案来测试临床预防试验中的疗效。
雌性 Fischer-344 大鼠（Harlan）用膀胱致癌剂 OH-BBN（TCI America，俄勒冈州波特兰）处理 8 周。大鼠用萘普生（400mg/kg 饮食）、阿司匹林（Sigma(R)）（300 或 3000mg/kg 饮食）、Iressa(R)（10mg/kg 吉非替尼体重每日）或白藜芦醇（1000mg/kg 饮食）治疗，使用 3 种方案中的 1 种，包括 1）OH-BBN 后 1 周开始并持续 7 个月，2）OH-BBN 后 3 个月出现显微镜下病变后并持续 3 个月，和 3）OH-BBN 后 1 周开始并持续 4 个月。在方案 1 和 2 中，膀胱病变重量和大肿瘤是主要终点，而在方案 3 中，显微镜下癌症是终点。
使用方案 1 萘普生、Iressa、白藜芦醇和低剂量和高剂量阿司匹林分别使大膀胱肿瘤的形成减少了 87%（减少）、90%（减少）、3%（增加）、6%（减少）和 60%（减少）。使用方案 2 Iressa 和萘普生也非常有效。方案 3 的评估表明，只有 Iressa 显著减少了显微镜下的膀胱癌（63%）。
在 OH-BBN 后开始治疗或膀胱病变已经存在时，萘普生和 Iressa 显示出预防大癌症形成的有效性。低剂量阿司匹林和白藜芦醇无效。在方案 3 中，显微镜下病变是终点，只有 Iressa 有效。因此，建立癌症终点似乎是更好的选择。具有良好心血管特征的萘普生或表皮生长因子受体抑制剂可能在辅助治疗中有效。
