Raghow S, Kuliyev E, Steakley M, Greenberg N, Steiner M S
University of Tennessee Urologic Research Laboratories, Memphis 38163, USA.
Cancer Res. 2000 Aug 1;60(15):4093-7.
Although the etiology of prostate cancer is still not clear, family history, hormones, and age are thought to play a role in its initiation and progression. There is no cure for the advanced disease. Because prostate cancer initially develops as an androgen-dependent tumor, agents with antiandrogen activity have become the focus for chemoprevention of this disease. A pilot study was undertaken to test the efficacy of flutamide (an antiandrogen) in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer. Three groups of mice received s.c. implantation of slow-release flutamide pellets: (a) low-dose flutamide group (6.6 mg/kg); (b) high-dose flutamide group (33 mg/kg); and (c) control placebo group. Efficacy was measured by the absence of palpable tumor formation. Prostate tissues/tumors were harvested for evaluation by molecular and histology techniques. The low-dose flutamide group did not differ significantly from the placebo group, in which palpable tumors initially presented at 17 weeks of age, and by 33 weeks, all of the animals developed palpable tumors. In the high-dose flutamide group, however, tumors did not appear until 24 weeks, a lag of 7 weeks, and by 34 weeks, 42% of the animals were still tumor free. The period of time at which 50% of the animals had tumors was 33 weeks in the high-dose flutamide group, 24.5 weeks in the low-dose flutamide group, and 24.5 weeks in the placebo group. The difference between the placebo and high-dose flutamide groups was statistically significant (log rank, P = 0.0036; Wilcoxon's statistical analysis, P = 0.0060). Tumors from high-dose flutamide-treated animals were more differentiated and retained much of the normal glandular architecture compared with those of the placebo group, whose tumors consisted of sheets of poorly differentiated cells. The expression of T antigen in the prostate tissues of flutamide-treated animals (at 10 weeks age) was lower than that in the comparable placebo-treated group. Flutamide had the ability to suppress T antigen-driven carcinogenesis, resulting in a significant decrease in the incidence of prostate cancer and an increase in the latency period of prostate cancer in TRAMP mice.
尽管前列腺癌的病因仍不明确，但家族史、激素和年龄被认为在其发生和发展过程中起作用。晚期前列腺癌无法治愈。由于前列腺癌最初是作为雄激素依赖性肿瘤发展的，具有抗雄激素活性的药物已成为这种疾病化学预防的焦点。进行了一项初步研究，以测试氟他胺（一种抗雄激素药物）在前列腺癌小鼠前列腺转基因腺癌（TRAMP）模型中的疗效。三组小鼠接受皮下植入缓释氟他胺微丸：（a）低剂量氟他胺组（6.6毫克/千克）；（b）高剂量氟他胺组（33毫克/千克）；以及（c）对照安慰剂组。通过未触及肿瘤形成来衡量疗效。采集前列腺组织/肿瘤，通过分子和组织学技术进行评估。低剂量氟他胺组与安慰剂组没有显著差异，安慰剂组在17周龄时开始出现可触及的肿瘤，到33周时，所有动物都出现了可触及的肿瘤。然而，在高剂量氟他胺组中，肿瘤直到24周才出现，延迟了7周，到34周时，42%的动物仍然没有肿瘤。高剂量氟他胺组中50%的动物出现肿瘤的时间为33周，低剂量氟他胺组为24.5周，安慰剂组为24.5周。安慰剂组和高剂量氟他胺组之间的差异具有统计学意义（对数秩检验，P = 0.0036；威尔科克森统计分析，P = 0.0060）。与安慰剂组相比，高剂量氟他胺治疗动物的肿瘤分化程度更高，保留了许多正常的腺结构，安慰剂组的肿瘤由成片的低分化细胞组成。氟他胺治疗动物（10周龄）前列腺组织中T抗原的表达低于相应的安慰剂治疗组。氟他胺有能力抑制T抗原驱动的致癌作用，导致TRAMP小鼠前列腺癌的发病率显著降低，前列腺癌的潜伏期延长。
