Transduction of a fiber-mutant adenovirus for the HSVtk gene highly augments the cytopathic effect towards gliomas.
Suicide gene therapy utilizing the herpes simplex thymidine kinase (HSVtk) / ganciclovir (GCV) system has been performed to kill cancer cells. However, the low transduction efficiency of HSVtk gene into cancer cells critically limits its efficacy in cancer treatment in clinical situations. To improve delivery of the HSVtk gene into cancer cells, we transduced U-87MG and U-373MG glioma cells with adenovirus (Adv) vectors with a fiber mutant, F / K20, which has a stretch of 20 lysine residues added at the C-terminus of the fiber, for the HSVtk gene (Adv-TK-F / K20), and compared the cytopathic effect of Adv-TK-F / K20 with that of the Adv for HSVtk with wild-type fiber (Adv-TK). The cytopathic effect of Adv-TK-F / K20 in U-87MG and U-373MG cells was approximately 140 and 40 times, respectively, stronger than that of Adv-TK. At the same multiplicity of infection (MOI) in each cell line, Adv-TK-F / K20 induced a higher degree of apoptosis (U-87MG, 35%; U-373MG, 77%) than Adv-TK (U-87MG, 0.11%; U-373MG, 27%) in U-87MG (MOI 0.03) and U-373MG cells (MOI 0.1). Cleavage of poly(ADP-ribose)polymerase (PARP) was more marked in the cells that were infected with Adv-TK-F / K20 than in cells that were infected with Adv-TK. These results indicate that gene therapy utilizing Adv-TK-F / K20 may be a promising therapeutic modality for the treatment of gliomas.
Shinoura
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Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Toshima-ku, Tokyo 170-8455, Japan. shinoura-k@komagome-hospital.bunkyo.tokyo.jp
Sakurai
S
S
Asai
A
A
Kirino
T
T
Hamada
H
H
D000256:Adenoviridae / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D010446:Peptide Fragments; D011065:Poly(ADP-ribose) Polymerases; D013937:Thymidine Kinase