2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice.
2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice.
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发表时间：
2001-10
期刊：
影响因子：
11.2
通讯作者：
J. Green;M. Shibata;E. Shibata;R. Moon;M. Anver;G. Kelloff;R. Lubet
中科院分区：
文献类型：
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作者：
J. Green;M. Shibata;E. Shibata;R. Moon;M. Anver;G. Kelloff;R. Lubet
在大鼠C3（1）基因调控下表达SV 40 T/t抗原的雌性转基因小鼠自发发生多灶性乳腺病变，可预见地演变为侵袭性、非依赖性乳腺癌，而雄性小鼠易于发生前列腺癌。对7 - 19周龄的雌性C3（1）/SV 40大T抗原小鼠给予化学预防剂，在此期间，乳腺病变发展并进展为浸润性癌。治疗2周或8周后，在接受单独溶媒、脱氢表雄酮（DHEA）或2-二氟甲基鸟氨酸（DFMO）的小鼠之间，未观察到浸润前乳腺上皮内瘤变病变（组织学上类似于人导管原位癌）数量的显著差异。然而，观察到DFMO（一种鸟氨酸脱羧酶抑制剂）和DHEA（灵长类动物中雄激素和雌激素的主要类固醇前体）在浸润性癌生长中的剂量反应减少。尽管转基因的表达没有改变，但DFMO（8000 mg/kg）和DHEA（4000 mg/kg; P < 0.05）使肿瘤发生率降低约20%和30%。DFMO和DHEA均使肿瘤多样性降低约50%（P < 0.05）。DFMO对总肿瘤负荷具有剂量依赖性作用，低剂量（4000 mg/kg）降低25%，高剂量（8000 mg/kg）降低70%。DHEA在低（2000 mg/kg）和高（4000 mg/kg）剂量下分别使肿瘤负荷降低50%和66%。有趣的是，尽管DHEA对肿瘤的发展有抑制作用，但它引起了血清雌二醇水平的剂量依赖性增加，我们以前已经证明，在这个模型中，它会增加乳腺肿瘤的形成。当用DHEA、DFMO、生育酚乙酸酯、硒代蛋氨酸或9-顺式-视黄酸处理小鼠时，未观察到对前列腺癌前体病变（前列腺上皮内瘤形成）的发展的影响，尽管未确定对晚期前列腺癌发展的影响。这些结果表明，尽管表达了高度转化的C3（1）/SV 40大T抗原转基因，但该转基因模型可用于研究化学预防剂对乳腺癌进展的影响。DHEA和DFMO对乳腺癌生长的肿瘤抑制作用似乎发生在浸润前病变的发展后，这表明这些药物抑制肿瘤进展，但不启动。
Female transgenic mice that express SV40 T/t antigens under the regulatory control of the rat C3(1) gene spontaneously develop multifocal mammary lesions that predictably evolve into invasive, hormone-independent carcinomas, whereas male mice are prone to develop prostate cancer. Chemopreventive agents were administered to female C3(1)/SV40 large T-antigen mice from 7 to 19 weeks of age, during which time the mammary lesions developed and progressed to invasive carcinomas. No significant differences in the numbers of preinvasive mammary intraepithelial neoplasia lesions (histologically similar to human ductal carcinoma in situ) were observed after 2 or 8 weeks of treatment between mice receiving either vehicle alone, dehydroepiandrosterone (DHEA), or 2-difluoromethylornithine (DFMO). However, a dose-response reduction in invasive carcinoma growth was observed for both DFMO, an inhibitor of ornithine decarboxylase, and DHEA, the primary steroid precursor to both androgens and estrogens in primates. Despite unaltered expression of the transgene, tumor incidence was reduced approximately 20% by DFMO (8000 mg/kg) and 30% by DHEA (4000 mg/kg; P < 0.05). Tumor multiplicity was reduced by approximately 50% by both DFMO and DHEA (P < 0.05). DFMO had a dose-dependent effect on total tumor burden, which was reduced by 25% at low doses (4000 mg/kg) and 70% at high doses (8000 mg/kg). DHEA reduced tumor burden by 50% and 66% at low (2000 mg/kg) and high (4000 mg/kg) doses, respectively. Interestingly, despite its inhibitory effects on tumor development, DHEA caused a dose-dependent increase of serum estradiol levels that we have previously shown to increase mammary tumor formation in this model. No effect on the development of the prostate cancer precursor lesions (prostate intraepithelial neoplasia) was observed when mice were treated with DHEA, DFMO, tocopherol acetate, selenomethionine, or 9-cis-retinoic acid, although the effects on late-stage prostate cancer development were not determined. These results demonstrate that despite the expression of the highly transforming C3(1)/SV40 large T-antigen transgene, this transgenic model can be used to study the effects of chemopreventive agents on mammary cancer progression. The tumor-inhibitory effects of DHEA and DFMO on mammary cancer growth appear to occur after the development of preinvasive lesions, suggesting that these agents inhibit tumor progression but not initiation.