Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. Quintin.Pan
Clin Cancer Res. 2009 Dec 1;15(23):7441-6. doi: 10.1158/1078-0432.CCR-09-1361. Epub 2009 Nov 24.
The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent.
Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice.
At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and >460 days for TM-treated mice (P < 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 +/- 6.2% and 50.9 +/- 4.5% (P < 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase-positive mammary stem cells in Her2/neu and FVB mammary glands.
Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment.
本研究旨在阐明四硫钼酸盐（TM）作为一种新型抗血管生成抗癌药物的疗效，作为一种化学预防剂。
无妊娠史的 Her2/neu 转基因小鼠用自来水或 TM 处理 180 天，并在治疗期间和治疗后 180 天观察肿瘤的发展情况。还观察了 TM 处理 Her2/neu 转基因和正常 FVB 小鼠后的乳腺组成和结构。
在 1 年的随访中，86.7%的对照和 40%的 TM 处理 Her2/neu 小鼠有可触及的乳腺肿瘤，肿瘤发展的中位时间为 234 天（95%置信区间，202-279 天）对照组和 TM 治疗组 >460 天（P <0.0005，n = 15）。TM 处理的 Her2/neu 和 FVB 小鼠的乳腺表现出上皮导管分支系统发育不良，由于次级分支数量和分化的乳腺上皮细胞总数明显减少。Her2/neu 和 FVB 乳腺中的微血管密度分别降低了 65.6%±6.2%和 50.9%±4.5%（P <0.005），与 TM 的抗血管生成作用一致。最后，TM 治疗导致 Her2/neu 和 FVB 乳腺中醛脱氢酶阳性乳腺干细胞的绝对数量增加了 2 倍。
综上所述，这些结果强烈支持 TM 是一种有效的化学预防剂，因为它通过调节乳腺干细胞池来重塑乳腺。
