Abstract 2509: Preclinical evaluation of the effects of cilengitide, an inhibitor of integrins, in sensitizing human solid cancer xenografts to radiation
Authors: Li Wang, David R. Valdecanas, David P. Molkentine, Luka Milas, Kathryn A. Mason, Kian K. Ang,, Uma Raju
Journal: Cancer Research (2011)

Abstract Purpose: Integrins are implicated in resistance of solid tumors to therapies, including radiation therapy, suggesting that their inhibition would enhance efficacy of tumor therapy. Because cilengitide, a cyclic Arg-Gly-Asp (RGD)-derived peptide, inhibits αVβ3 and αVβ5 integrins, we investigated the efficacy of cilengitide in enhancing in vitro cancer cell radiosensitivity and in vivo radioresponse of cancer xenografts. Methods: Three non-small cell lung carcinoma lines (NSCLCs) (H460, A549 and H1299) and five head and neck squamous cell carcinoma lines (HNSCCs) (FaDu, SCC-15, SCC-25, HN-5 and UMSCC-1) cell lines were used for in vitro experiments. Of these, H460 and FaDu were used for in vivo testing when grown as xenografts in nude mice. The effects of cilengitide (1 – 50 µg/ml, 24 h) on in vitro cell viability was determined by MTS assay and on cellular radiosensitivity by clonogenic cell survival assay after exposing the cells to graded single doses of γ-radiation with or without cilengitide (given 1 h before and continued for 23 h after irradiation). In vivo effect of cilengitide on radioresponse of xenografts was assessed by tumor growth delay. When tumor xenografts reached 7 mm in diameter cilengitide treatment (30 or 60 mg/d/5days) was initiated followed by a single dose of 15 Gy local radiation (using 137Cs γ-ray source), when the tumors reached 8 mm. Results: Cilengitide (5µg/ml, 24 h) reduced in vitro viability of 7 out of 8 cell lines tested, which ranged between 71.4 ± 2.2% (SCC-15) and 27.8 ± 4.2% (H1299). In general, NSCLCs were more sensitive to cilengitide than HNSCCs. When combined with radiation, cilengitide significantly enhanced the radiosensitivity of all 3 NSCLC, by enhancement factors of 1.35 for H460, 1.56 for A549 and 1.3 for H1299. In contrast, cilengitide exerted only an additive effect on radiosensitivity of HNSCC lines. In vivo experiments showed that cilengitide as a single agent had no antitumor activity, but in combination with radiation it significantly enhanced response of both H460 (NSCLC) and FaDu (HNSCC) tumor xenografts. The enhancement factors were 1.7 for H460 and 2.0 for FaDu. Conclusion: The results showed that cilengitide reduced in vitro cell viability of lung and head and neck cancer cells but had no effect on tumor growth in vivo. When combined with radiation, the drug enhanced radiosensitivity of lung but not head and neck carcinoma cells. In contrast, cilengitide was highly effective in enhancing radiation response of both lung (H460) and head and neck (FaDu) tumor xenografts. These results suggest that cilengitide has potential to improve the treatment outcome of patients with NSCLC and HNSCC when combined with radiotherapy. Mechanistic studies addressing cilengitide-radiation interactions both in vitro and in vivo are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2509. doi:10.1158/1538-7445.AM2011-2509