The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma.Glioblastoma is the most common malignant tumor of the central nervous system. 1 Currently, microsurgery and adjuvant concomitant chemoradiotherapy with temozolomide are the recommended first-line treatment for patients with primary glioblastoma.2 Despite recent advances in the treatment of glioblastoma, the prognosis for patients with newly diagnosed glioblastoma remains dismal; hence, these patients survive for no more than 2 years after diagnosis. Currently, there are no proven effective therapeutic options against temozolomide resistance. Therefore, there is a great interest in finding novel therapeutic agents for overcoming the resistance to temozolomide.Cilengitide (EMD121974), a cyclic Arg-Gly-Asp (RGD)-based peptide, is an antagonist of integrins avb3 and avb5 and has been thought to primarily exert an antiangiogenic effect on malignant glioma cells.3 Moreover, cilengitide may also have a direct effect on attachment, migration, invasion and viability of tumor cells. 4 Recently, cilengitide has become of great interest as a novel therapeutic agent for primary and recurrent glioblastoma. [4][5][6][7] Preliminary reports suggested that cilengitide exhibited a preferential benefit over the current concomitant chemoradiotherapy with temozolomide in patients with O 6 -methyl-guanine DNA methyltransferase (MGMT) promoter methylation. 8 Belotecan showed greater antitumor activity while exhibiting a reduced toxicity profile compared to irinotecan or topotecan in recent clinical tr...

The prognosis and the clinical course for glioblastoma patients remain dismal in spite of various multidisciplinary approaches of treatment, such as concurrent chemoradiotherapy with temozolomide. Especially, the resistance to temozolomide of primary or recurrent glioblastoma is the significant obstacle to the cure of this tumor. In the present study, we evaluated the in vitro and in vivo antitumor effect of cilengitide in combination with CKD-602, a camptothecin derivate, for experimental glioblastoma. The combination treatment with cilengitide and CKD-602 enhanced the cytotoxic effects to the glioblastoma cell lines, including U87MG and U251MG and increased the proportion of apoptosis of the tumor cells, compared with the monotherapy with either drug. Nude mice with established U87MG glioblastoma were assigned to the 4 groups; control group (injection with saline only), 2 cilengitide group (injection with a dose of cilengitide at 2 mg/mL), CKD-602 group (injection with a dose of CKD-602 at 2 mg/mL), and combination group. In animals with combination therapy, the significant reduction of tumor volume was demonstrated (p &lt; 0.05). The immunohistochemistry with CD31 and Annexin-V showed that this synergistic effect was caused by the decrease of angiogenesis by cilengitide and the increase of apoptosis by CKD-602. Cilengitide in combination with CKD-602 could be an alternative treatment option for glioblastoma. Keywords; glioblastoma; cilengitide; CKD-602; angiogenesis; apoptosis Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2353. doi:1538-7445.AM2012-2353