Combined Radiation Sensitizing and Anti-angiogenic Effects of Ionizing Radiation and the Protease Inhibitor Ritonavir in a Head and Neck Carcinoma Model

• Published in: Anticancer research 2005-11, Vol.25 (6B), p.4357-4362
• Main Authors: Maggiorella, Laurence, Wen, Bixiu, Frascogna, Valerie, Opolon, Paule, Bourhis, Jean, Deutsch, Eric
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - radiation effects; Biological and medical sciences; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - radiotherapy; Cell Growth Processes - drug effects; Cell Growth Processes - radiation effects; Cell Line, Tumor; Cellular Biology; Combined Modality Therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Experimental tumors, general aspects; Female; Head and Neck Neoplasms - blood supply; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - radiotherapy; Humans; Life Sciences; Medical sciences; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - radiotherapy; Pharmacology. Drug treatments; Radiation-Sensitizing Agents - pharmacology; Ritonavir - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0250-7005; 1791-7530

Ritonavir, a protease inhibitor, has been successfully applied in the treatment of HIV infection. Reports of dramatic improvement of AIDS-related cancers, such as primary central system lymphoma after radiation therapy as well as Kaposi's sarcoma, led to the recent discovery of the “non viral” antitumor activity of HIV protease inhibitors. This study was designed to detect the antitumor effect of Ritonavir when combined with ionizing radiation both in vitro and in vivo in the HEP-2 head and neck carcinoma model. Inhibition of tumor growth was observed when mice were treated with Ritonavir alone and this effect was enhanced when combined with ionizing radiation. No adverse effect or significant toxicity in the hosts' body weights was seen between the different treatment and control groups throughout the experiments. A marked antiproliferation effect of the combination was observed in vitro. A marked reduction of angiogenesis was detected within the tumor sections from the Ritonavir combined with irradiation group as compared with the Ritonavir or irradiation alone groups. Western blot analysis showed that apoptosis was induced by an increased expression of Bax and decreased expression of Bcl-2 after treatment with Ritonavir and ionizing radiation. Thus, the antitumor effect of the latter combination is associated with the enhancement of radiation-induced apoptosis and inhibition of angiogenesis. These data suggested that Ritonavir could clinically improve the tumor response to radiation therapy, especially in head and neck carcinoma.