Cilengitide TFA

Cilengitide is a potent and selective integrin inhibitor for αvβ3 and αvβ5 receptor, with IC50 values of 4 nM and 79 nM, respectively.

Research Areas >> Cancer

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Cytoskeleton >> Integrin

IC50: 4/79 nM (αvβ3/αvβ5)[1].

Cilengitide (EMD 121974) is the αvβ3 and αvβ5 integrin receptor antagonist. In cell adhesion studies assessing the human melanoma M21 or UCLA-P3 human lung carcinoma cell lines, Cilengitide inhibits integrin-mediated binding to vitronectin with IC50s of 0.4 and 0.4 μM[1]. In vitro treatment of Cilengitide, at a concentration greater than 1 µM, shows concentration- and time-dependent cytotoxic effects [2].

In nude mice bearing M21-L melanoma tumors, Cilengitide dose i.p. at 10, 50, and 250 μg three times per week demonstrate inhibition of tumor growth with a reduction in both tumor volume (55%, 75%, and 89%, respectively) and tumor weight (23%, 38%, and 61%, respectively), when compared to controls[2]. In the rat model studied, the systemic pharmacokinetics of i.p. Cilengitide are not affected by ILP with Cilengitide alone or ILP with Cilengitide plus Melphalan, TNF or both. Systemic Cilengitide levels reach around 20 µg/mL (approximately 35 µM) within 10 min of i.p. administration and continued to rise to approximately 40 µg/mL (approximately 70 µM) in the first hour. Thereafter Cilengitide levels in serum drop with an elimination half-life of 2.1 hr[3].

The cytotoxicity of the two drugs, Belotecan and Cilengitide, is measured by the Cell Counting Kit-8 (CCK-8). U87MG and U251MG cells are seeded in 96 well plates at a density of 4×103 cells per well to allow for adhesion overnight. After this, the cells are treated with Cilengitide at a concentration of 0, 0.1, 0.5, 1, 5 and 25 µM and Belotecan at a concentration of 0, 6.25, 12.5, 25, 50 and 100 nM. All possible combinations of concentrations are used to assess the combined therapeutic effect of Cilengitide and Belotecan. After 3 days, 10 µL of the CCK-8 solution is added to each well of the plate, and the plate is incubated for 3 hr in the incubator (37°C; 5% CO2)[2].

Mice[2] Male Balb/c-nu mice, at 8 weeks of age, are randomly assigned to four groups: control (n=10), Cilengitide (n=10), Belotecan (n=10) and combination (n=10). Cilengitide is administered intraperitoneally at a dose of 20 mg/kg daily and the Belotecan at a dose of 10 mg/kg every 4 days. The drug treatments began 7 days after the implantation of tumor cells for 16 days. Half of the animals are sacrificed 1 month after the implantation of the tumor cells for tumor volume analysis and the rest of the animals are observed for another 2 months to analyze survival. The death of the animals is defined as a weight reduction of over 25% of the initial weight or an unexpected sudden death beforehand[2].

[1]. Hariharan S, et al. Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrinreceptor antagonist, Cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol. 2007 Aug;18(8):1400-7.

[2]. Kim YH, et al. Combination therapy of cilengitide with belotecan against experimental glioblastoma. Int J Cancer. 2013 Aug 1;133(3):749-56.

[3]. Ten Hagen TL, et al. The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model. Int J Cancer. 2012 Nov 13.