Department of Clinical Sciences, James L. Voss Veterinary Teaching Hospital, Colorado State University Animal Cancer Center, Fort Collins, CO 80525, USA.
Cancer Chemother Pharmacol. 2011 Jan;67(1):83-92. doi: 10.1007/s00280-010-1287-z. Epub 2010 Mar 20.
Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS.
We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model.
Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Pre-incubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model.
These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.
骨肉瘤（OS）在许多患者中仍然是一种无法治愈且最终致命的疾病，因此需要新的治疗方法。更接近人类疾病的新型 OS 模型将为新型疗法的效用提供更可靠的信息。犬自发性 OS 可能提供这样的模型。组蛋白去乙酰化酶（HDAC）抑制剂的药理抑制具有多种抗肿瘤作用，但与标准细胞毒性疗法联合使用时可能具有最大的效用。我们试图确定组蛋白去乙酰化酶抑制剂丙戊酸（VPA）对犬和人骨肉瘤中多柔比星（DOX）敏感性的体外和体内作用。
我们评估了 VPA/DOX 联合治疗的体外抗增殖和促凋亡作用、VPA 治疗导致的组蛋白乙酰化和核 DOX 积累的变化，以及组合疗法在异种移植模型中的体内疗效。
用临床可行的 VPA 浓度处理犬和人骨肉瘤细胞系导致组蛋白乙酰化增加，但抗增殖作用适度。VPA 预孵育后再用多柔比星（DOX）处理导致明显的生长抑制和促凋亡作用，与核 DOX 积累的剂量依赖性增加相关。VPA 和 DOX 的联合治疗在犬骨肉瘤异种移植模型中优于单一疗法。
这些结果表明，在当前 OS 治疗方案中添加 HDAC 抑制剂具有合理性，并说明了 HDAC 抑制剂在人骨肉瘤和犬骨肉瘤之间的反应相似性，进一步证明了犬骨肉瘤模型的可信度。
