Chen Ping, Yang Ling-Lin, Yang Han-Shuo, Wang Yong-Sheng, Li Gang, Wu Yang, Fang Fang, Liu Kang, Li Jie, Zhao Xia, Hu Huo-Zhen, Wei Yu-Quan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan 610041, People's Republic of China.
J Cancer Res Clin Oncol. 2008 Jun;134(6):679-87. doi: 10.1007/s00432-007-0337-3. Epub 2007 Dec 8.
IFN-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) has been described as an antiangiogenic chemokine and displays a potent antitumor activity in vivo. In the present study, we try to investigate whether the combination therapy of hyperthermia, a physical antiangiogenic modality, with CXCL10 would completely eradicate the established solid tumors.
Immunocompetent BALB/c mice bearing Meth A fibrosarcoma were established. Mice were treated with either CXCL10 at 25 microg/kg once a day for 20 days, hyperthermia was given twice (at 42 degrees C for 1 h, on day 6 and 12 after the initiation of CXCL10), or together. Tumor volume and survival time were observed. The microvessel density was determined by CD31 immunofluorescence. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues.
The results showed that CXCL10 and hyperthermia inhibited the growth of Meth A fibrosarcoma and interestingly, the combination therapy enhanced the antiangiogenic effects and completely eradicated the established solid tumors. Histological examination revealed that CXCL10 + hyperthermia led to increased induction of apoptosis, tumor necrosis, and elevated lymphocyte infiltration compared with the controls. Moreover, the tumor eradicated animals developed a protective T-cell-dependent antitumor memory response against Meth A tumor cells rechallenge.
Our finding is that the combination therapy can achieve a synergistic antitumor efficacy, supporting the idea that the combination of two antiangiogenic agents may lead to improved clinical outcome. These findings could open new perspectives in clinical antitumor therapy.
干扰素诱导蛋白10（IP - 10）/CXC趋化因子配体10（CXCL10）已被描述为一种抗血管生成趋化因子，并在体内显示出强大的抗肿瘤活性。在本研究中，我们试图探究热疗（一种物理抗血管生成方式）与CXCL10的联合治疗是否能完全根除已形成的实体瘤。
建立携带Meth A纤维肉瘤的免疫活性BALB/c小鼠模型。小鼠分别接受以下处理：每天一次给予25μg/kg的CXCL10，共20天；热疗进行两次（在CXCL10开始给药后的第6天和第12天，42℃持续1小时）；或两者联合使用。观察肿瘤体积和生存时间。通过CD31免疫荧光法测定微血管密度。还对肿瘤组织进行了组织学分析和凋亡细胞评估。
结果显示，CXCL10和热疗均抑制了Meth A纤维肉瘤的生长，有趣的是，联合治疗增强了抗血管生成作用，并完全根除了已形成的实体瘤。组织学检查显示，与对照组相比，CXCL10 + 热疗导致凋亡诱导增加、肿瘤坏死以及淋巴细胞浸润增加。此外,肿瘤被根除的动物对再次攻击的Meth A肿瘤细胞产生了保护性的T细胞依赖性抗肿瘤记忆反应。
我们的发现是联合治疗可实现协同抗肿瘤疗效，支持两种抗血管生成药物联合使用可能改善临床结局的观点。这些发现可能为临床抗肿瘤治疗开辟新的前景。
