Department of Gynecologic Oncology, Henan Cancer Hospital, Zhengzhou, Henan, China.
PLoS One. 2011;6(9):e24405. doi: 10.1371/journal.pone.0024405. Epub 2011 Sep 9.
MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. We previously reported that anti-MUC1 monoclonal antibody C595 (MAb C595) plus docetaxel (DTX) increased efficacy of DTX alone and caused cultured human epithelial ovarian cancer (EOC) cells to undergo apoptosis. To further study the mechanisms of this combination-mediated apoptosis, we investigated the effectiveness of this combination therapy in vivo in an intraperitoneal (i.p.) EOC mouse model. OVCAR-3 cells were implanted intraperitoneally in female athymic nude mice and allowed to grow tumor and ascites. Mice were then treated with single MAb C595, DTX, combination test (MAb C595 and DTX), combination control (negative MAb IgG(3) and DTX) or vehicle control i.p. for 3 weeks. Treated mice were killed 4 weeks post-treatment. Ascites volume, tumor weight, CA125 levels from ascites and survival of animals were assessed. The expression of MUC1, CD31, Ki-67, TUNEL and apoptotic proteins in tumor xenografts was evaluated by immunohistochemistry. MAb C595 alone inhibited i.p. tumor growth and ascites production in a dose-dependent manner but did not obviously prevent tumor development. However, combination test significantly reduced ascites volume, tumor growth and metastases, CA125 levels in ascites and improved survival of treated mice compared with single agent-treated mice, combination control or vehicle control-treated mice (P<0.05). The data was in a good agreement with that from cultured cells in vitro. The mechanisms behind the observed effects could be through targeting MUC1 antigens, inhibition of tumor angiogenesis, and induction of apoptosis. Our results suggest that this combination approach can effectively reduce tumor burden and ascites, prolong survival of animals through induction of tumor apoptosis and necrosis, and may provide a potential therapy for advanced metastatic EOC.
MUC1 与细胞转化和致瘤性相关，被认为是癌症治疗的重要肿瘤相关抗原 (TAA)。我们之前报道过，抗 MUC1 单克隆抗体 C595（MAb C595）加多西紫杉醇（DTX）增加了 DTX 的疗效，并导致培养的人上皮性卵巢癌（EOC）细胞发生凋亡。为了进一步研究这种组合介导的凋亡的机制，我们在腹腔（i.p.）EOC 小鼠模型中研究了这种组合疗法的体内效果。将 OVCAR-3 细胞腹腔内植入雌性无胸腺裸鼠体内，使其生长肿瘤和腹水。然后，用单 MAb C595、DTX、联合试验（MAb C595 和 DTX）、联合对照（阴性 MAb IgG(3) 和 DTX）或 i.p. 载体对照治疗 3 周。治疗后 4 周处死小鼠。评估腹水体积、肿瘤重量、腹水 CA125 水平和动物的存活率。通过免疫组织化学评估肿瘤异种移植物中 MUC1、CD31、Ki-67、TUNEL 和凋亡蛋白的表达。MAb C595 单独以剂量依赖性方式抑制 i.p.肿瘤生长和腹水产生，但不能明显阻止肿瘤发展。然而，与单药治疗组、联合对照或载体对照治疗组相比，联合试验显著减少腹水体积、肿瘤生长和转移、腹水 CA125 水平，并改善治疗小鼠的存活率（P<0.05）。数据与体外培养细胞的结果一致。观察到的效果背后的机制可能是通过靶向 MUC1 抗原、抑制肿瘤血管生成和诱导细胞凋亡。我们的结果表明，这种联合方法可以通过诱导肿瘤凋亡和坏死有效减少肿瘤负担和腹水，延长动物的存活时间，为晚期转移性 EOC 提供一种潜在的治疗方法。
