Abstract
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 IgG3 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.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and the fifth most common cause of cancer-related deaths in women in the United States, resulting in an estimated 21,880 new cases and 13,850 deaths in 2009 [1]
These results suggest that combination treatments with monoclonal antibodies (MAbs) C595 and DTX or with control MAb IgG3 and DTX could be safely used in animal models to study efficacy
We further investigated whether MAb C595, combined with DTX, would be more efficient than DTX alone in killing EOC tumors in a xenograft animal mode previously developed by our laboratory [28]
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and the fifth most common cause of cancer-related deaths in women in the United States, resulting in an estimated 21,880 new cases and 13,850 deaths in 2009 [1]. Patients with advanced disease have a response rate of more than 80% following surgery and adjuvant chemotherapy with platinum-taxane, with a median progression-free interval of 18 months [2]. The cancer will recur in the majority of these patients, and the overall 5-year survival rate for patients with advanced stage disease is only 23–30% [3]. Conventional cancer chemotherapy often results in severe side effects related to non-specific modes of action. Studies evaluating various cytotoxic agents in recurrent EOC have found response rates of 10–28% with an accompanying progressive increase in the number of drug-resistant tumors [4]. Novel therapeutic strategies are urgently needed to improve the outcome for this deadly disease. A promising approach that may improve patient outcome is the use of monoclonal antibodies (MAbs) combined with traditional chemotherapy
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