Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma
Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma
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DOI：
10.1158/1078-0432.ccr-07-0014
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发表时间：
2007-08-01
影响因子：
11.5
通讯作者：
Pili, Roberto
中科院分区：
文献类型：
--
作者：
Kato, Yukihiko;Yoshimura, Kiyoshi;Pili, Roberto
目的：大剂量白介素2(IL-2)是美国食品和药物管理局(FDA)批准的治疗转移性肾癌的方案。然而，与IL-2相关的毒性和有限的临床益处阻碍了它的使用。组蛋白脱乙酰酶(HDAC)抑制剂已被证明在包括肾癌在内的不同肿瘤模型中具有抗肿瘤活性，并具有免疫调节特性。在我们的研究中，我们测试了IL-2和HDAC抑制剂MS-275在小鼠肾细胞癌(RECA)模型中的联合治疗效果。实验设计：将表达RECA荧光素酶的细胞植入BALB/C小鼠的左肾。动物随机分为4组，每组各1只，每日2次，每次15万IU。每周两次注射，每日口服MS-275 5 mg/kg(5d/wk)，或联合应用。结果：与IL-2(无明显抑制)或MS-275(相当于40%抑制率)相比，联合治疗2周后的荧光素酶图像和肿瘤重量显示出明显的抑瘤率(80%)。与单一治疗组相比，联合治疗组的自发性肺转移也受到抑制(抑制率为90%)。Kaplan-Meier分析显示，与对照组和单一药物相比，联合治疗组的存活率在统计学上显著提高。联合处理的小鼠的脾细胞比单一药物处理的小鼠的脾细胞对Renca细胞的裂解作用更强。联合应用MS-275和IL-2后，荷瘤动物的淋巴组织中CD4(+)CD25(+)T细胞和Foxp3(+)T细胞(T调节细胞)的百分率分别增加或降低。CD8(+)T细胞的耗竭降低了MS-275+IL-2联合应用的生存优势。结论：在免疫功能正常的小鼠肾癌模型中，联合应用IL-2和MS-275具有协同抗肿瘤作用。其抗肿瘤作用与降低T调节细胞数量和增强脾细胞的抗肿瘤细胞毒作用有关。总之，这些临床前数据为临床测试联合应用IL-2和HDAC抑制剂治疗肾癌患者提供了理论依据。
Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration - approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model.Experimental Design: RENCA luciferase - expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection.Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (similar to 40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytesfrom mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4(+)CD25(+) Tcells and Foxp3(+) Tcells (Tregulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8(+) T cells abrogated the survival benefit from MS-275 + IL-2 combination.Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.