title: Tumor therapy by gene regulation system responding to cellular signal.
abstract: For safe and efficient gene therapy, the development of gene delivery systems to specifically target tumor cells is one of the most important issues regarding present gene delivery methodologies. Recently, we have developed a novel drug or gene delivery system responding to cellular signals (D-RECS) that can activate transgenes in response to hyperactivated cellular signals. Especially, a protein kinase C (PKC)α-responsive polymeric carrier (polymer-peptide conjugate, PPC(S)) showed highly specific gene expression to tumor cells and tissues. In the present study, we have applied the PKCα-responsive polymeric carrier to tumor gene therapy. PPC(S) consists of a polyacrylamide backbone and cationic peptide side chains, which together make PPC(S) as a positive polymer, a PKCα-specific substrate. A negative control polymer, PPC(A), was also prepared by replacing a serine residue at the phosphorylation site of the peptide side chains of PPC(S) with alanine. A complex of PPC(S) with caspase-8 or the herpes simplex virus-thymidine kinase (HSV-TK) gene as therapeutic genes was transfected into certain tumor cells or tissues. The prodrug ganciclovir (GCV) was then intraperitoneally injected into PPC(S)/HSV-TK complex-transfected mice. The PPC(S)/gene complex showed significant cytotoxicity toward the tumor cells and suppression of tumor growth, compared with those of the PPC(A)/gene complex or PBS. These results indicate that the PKCα-responsive polymeric carrier is applicable for tumor-targeted gene therapy.
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan.
authors: Tetsuro
authors: T
authors: Tomiyama
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan.
authors: Riki
authors: R
authors: Toita
authors: Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan.
authors: Jeong-Hun
authors: JH
authors: Kang
authors: Department of Microbiology St. Marianna University School of Medicine 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
authors: Daisuke
authors: D
authors: Asai
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan.
authors: Shujiro
authors: S
authors: Shiosaki
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan.
authors: Takeshi
authors: T
authors: Mori
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan.
authors: Takuro
authors: T
authors: Niidome
authors: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka 819-0395, Japan. Electronic address: ykatatcm@mail.cstm.kyushu-u.ac.jp.
authors: Yoshiki
authors: Y
authors: Katayama
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D010766:Phosphorylation; D011108:Polymers / Q000008:administration & dosage*; D051571:Protein Kinase C-alpha / Q000502:physiology*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection
chemical_list: D011108:Polymers; D004247:DNA; D013937:Thymidine Kinase; D051571:Protein Kinase C-alpha; D053181:Caspase 8; D015774:Ganciclovir