Woditschka Stephan, Haag Jill D, Sullivan Ruth, Gould Michael N
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
Cancer Prev Res (Phila). 2009 Feb;2(2):153-60. doi: 10.1158/1940-6207.CAPR-08-0114.
Preclinical models that accurately reproduce specific aspects of human disease etiology are invaluable for the initial development and evaluation of chemopreventive agents. We developed a novel, short-term prevention model, which is particularly useful for assessing the efficacy of a compound to prevent hormonally responsive and nonresponsive in situ carcinomas. In this model, carcinogenesis is induced by a high titer of neu-containing, replication-defective retrovirus. The multiplicity and size of the resulting in situ carcinomas are scored in whole-mounted, aluminum carmine-stained mammary glands at 15 days postinfusion. These in situ carcinomas represent a distinct biological time point in the development of neu-induced mammary cancer in the rat. They are characterized by high rates of proliferation (40.0%; P < 0.0001) and apoptosis (2.8%; P < 0.005) compared with mammary carcinomas. The majority of in situ carcinomas regress spontaneously after 20 days postinfusion. The in situ carcinomas at 15 days postinfusion exhibit hormonal responsiveness. The effects of the chemoprevention agents tamoxifen, celecoxib, and targretin on hormonally responsive and nonresponsive in situ carcinomas recapitulate those observed on mammary carcinomas at 12 and 18 weeks postinfusion for intact and ovariectomized rats, respectively. Neu-induced in situ carcinomas in the rat represent etiologically relevant intermediate time points of mammary carcinogenesis. Our prevention model represents a cost-efficient in vivo system to determine whether the preventive effects of a compound extend to hormonally nonresponsive mammary lesions, for which new chemoprevention approaches are needed.
能够准确重现人类疾病病因学特定方面的临床前模型，对于化学预防剂的初步开发和评估而言具有极高价值。我们开发了一种新型短期预防模型，该模型对于评估化合物预防激素反应性和非激素反应性原位癌的疗效尤为有用。在这个模型中，通过高滴度含neu的复制缺陷型逆转录病毒诱导致癌作用。在输注后15天，对全装、经铝卡红染色的乳腺中产生的原位癌的数量和大小进行评分。这些原位癌代表了大鼠neu诱导的乳腺癌发展过程中一个独特的生物学时间点。与乳腺癌相比，它们的特征是增殖率高（40.0%；P<0.0001）和凋亡率高（2.8%；P<0.005）。大多数原位癌在输注后20天会自发消退。输注后15天的原位癌表现出激素反应性。化学预防剂他莫昔芬、塞来昔布和贝沙罗汀对激素反应性和非激素反应性原位癌的作用，分别概括了在输注后12周和18周对完整和去卵巢大鼠乳腺癌所观察到的作用。大鼠neu诱导的原位癌代表了乳腺致癌过程中与病因相关的中间时间点。我们的预防模型代表了一种经济高效的体内系统，用于确定化合物的预防作用是否扩展到激素无反应性乳腺病变，而对于这种病变需要新的化学预防方法。
