DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs.
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.
Shinohara
Eric T
ET
Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.
Geng
Ling
L
Tan
Jiahui
J
Chen
Heidi
H
Shir
Yu
Y
Edwards
Eric
E
Halbrook
James
J
Kesicki
Edward A
EA
Kashishian
Adam
A
Hallahan
Dennis E
DE
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases