Antisense ATM gene therapy: a strategy to increase the radiosensitivity of human tumors.
Atm, the gene mutated in ataxia-telangiectasia (AT) patients, is an essential component of the signal transduction pathway that responds to DNA damage due to ionizing radiation (IR). We attenuated ATM protein expression in human glioblastoma cells by expressing antisense RNA to a functional domain of the atm gene. While ATM expression decreased, constitutive expression of p53 and p21 increased. Irradiated ATM-attenuated cells failed to induce p53, demonstrated radioresistant DNA synthesis, and increased radiosensitivity. Antisense-ATM gene therapy in conjunction with radiation therapy may provide a novel strategy for the treatment of cancer.
Guha
C
C
Department of Radiation Oncology of the Albert Einstein College of Medicine, New York, NY, USA.
Guha
U
U
Tribius
S
S
Alfieri
A
A
Casper
D
D
Chakravarty
P
P
Mellado
W
W
Pandita
T K
TK
Vikram
B
B
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016372:RNA, Antisense / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016372:RNA, Antisense; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases