Palmieri Diane, Lockman Paul R, Thomas Fancy C, Hua Emily, Herring Jeanne, Hargrave Elizabeth, Johnson Matthew, Flores Natasha, Qian Yongzhen, Vega-Valle Eleazar, Taskar Kunal S, Rudraraju Vinay, Mittapalli Rajendar K, Gaasch Julie A, Bohn Kaci A, Thorsheim Helen R, Liewehr David J, Davis Sean, Reilly John F, Walker Robert, Bronder Julie L, Feigenbaum Lionel, Steinberg Seth M, Camphausen Kevin, Meltzer Paul S, Richon Victoria M, Smith Quentin R, Steeg Patricia S
Women's Cancers Section, Laboratory of Molecular Pharmacology, Genetics Branch, National Cancer Institute/NIH, Bethesda, Maryland, USA.
Clin Cancer Res. 2009 Oct 1;15(19):6148-57. doi: 10.1158/1078-0432.CCR-09-1039. Epub 2009 Sep 29.
As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer.
The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo.
Following systemic administration, uptake of [(14)C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52.
We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation.
随着化疗和分子治疗提高了乳腺癌患者的全身生存率，脑转移的发生率也在增加。由于血脑屏障严重限制药物进入，治疗脑转移的治疗策略很少。我们报告了组蛋白脱乙酰酶抑制剂伏立诺他（辛二酰苯胺异羟肟酸）在三阴性乳腺癌脑转移临床前模型中的药代动力学、疗效及作用机制研究。
将MDA-MB-231人乳腺癌细胞系的231-BR脑营养亚系注射到免疫缺陷小鼠体内进行药代动力学和转移研究。药效学研究比较了体内外组蛋白乙酰化、细胞凋亡、增殖和DNA损伤情况。
全身给药后[(14)C]伏立诺他在正常啮齿动物脑中的摄取显著，在由231-BR细胞形成的一部分转移灶中的蓄积高达3倍。与注射后第3天开始用赋形剂治疗的小鼠相比，伏立诺他可使231-BR微转移灶的发生减少28%（P = 0.017），大转移灶减少62%（P < 0.0001）。伏立诺他作为单一药物的抑制活性与体内一种新功能有关：诱导与DNA修复基因Rad52下调相关的DNA双链断裂。
我们报告了预防三阴性乳腺癌脑转移的首个临床前数据。伏立诺他可透过血脑屏障，能预防62%的脑转移形成。其作用机制涉及诱导DNA双链断裂，提示可与DNA活性药物或放疗进行合理联合。
