DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 12; pp. 4987 - 4992
• Main Authors: SHINOHARA, Eric T, LING GENG, JIAHUI TAN, HEIDI CHEN, YU SHIR, EDWARDS, Eric, HALBROOK, James, KESICKI, Edward A, KASHISHIAN, Adam, HALLAHAN, Dennis E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.2005
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - radiotherapy; Cell Growth Processes - drug effects; Cell Growth Processes - radiation effects; Cell Line, Tumor; Combined Modality Therapy; DNA-Activated Protein Kinase; DNA-Binding Proteins - antagonists & inhibitors; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - radiation effects; Medical sciences; Melanoma, Experimental - blood supply; Melanoma, Experimental - drug therapy; Melanoma, Experimental - enzymology; Melanoma, Experimental - radiotherapy; Mice; Mice, Nude; Mice, SCID; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - radiotherapy; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Radiation-Sensitizing Agents - pharmacology; Tumors; Drug; Protein kinase A; Target; Targeting; DNA; Radiation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-4250

DNA-dependent protein kinase (DNA-PK)-defective severe combined immunodeficient (SCID) mice have a greater sensitivity to ionizing radiation compared with wild-type mice due to deficient repair of DNA double-strand break. SCID cells were therefore studied to determine whether radiosensitization by the specific inhibitor of DNA-PK, IC87361, is eliminated in the absence of functional DNA-PK. IC87361 enhanced radiation sensitivity in wild-type C57BL6 endothelial cells but not in SCID cells. The tumor vascular window model was used to assess IC87361-induced radiosensitization of SCID and wild-type tumor microvasculature. Vascular density was 5% in irradiated SCID host compared with 50% in C57BL6 mice (P < 0.05). IC87361 induced radiosensitization of tumor microvasculature in wild-type mice that resembled the radiosensitive phenotype of tumor vessels in SCID mice. Radiosensitization by IC87361 was eliminated in SCID tumor vasculature, which lack functional DNA-PK. Irradiated LLC and B16F0 tumors implanted into SCID mice showed greater tumor growth delay compared with tumors implanted into either wild-type C57BL6 or nude mice. Furthermore, LLC tumors treated with radiation and IC87361 showed tumor growth delay that was significantly greater than tumors treated with radiation alone (P < 0.01 for 3 Gy alone versus 3 Gy + IC87361). DNA-PK inhibitors induced no cytotoxicity and no toxicity in mouse normal tissues. Mouse models deficient in enzyme activity are useful to assess the specificity of novel kinase inhibitors. DNA-PK is an important target for the development of novel radiation-sensitizing drugs that have little intrinsic cytotoxicity.