Fiber-mutant technique can augment gene transduction efficacy and anti-tumor effects against established murine melanoma by cytokine-gene therapy using adenovirus vectors.
Melanoma cells are relatively resistant to adenovirus vector (Ad)-mediated gene transfer due to the low expression of Coxsackie-adenovirus receptor (CAR), which acts as a primitive Ad-receptor. Therefore, extremely high doses of Ad are required for effective gene therapy against melanoma. In the present study, we investigated whether fiber-mutant Ad containing the Arg-Gly-Asp (RGD) sequence in the fiber knob could promote gene delivery and anti-tumor effects in the murine B16 BL6 tumor model. B16 BL6 cells (in vitro) and tumors (in vivo) infected with RGD fiber-mutant Ad containing a tumor necrosis factor alpha gene (Ad-RGD-TNFalpha) produced more TNFalpha than those infected with conventional Ad-TNFalpha. In addition, Ad-RGD-TNFalpha required about one-tenth the dosage of Ad-TNFalpha for induction of equal therapeutic effects upon intratumoral injection into established B16 BL6 tumors. Furthermore, the combination of both TNFalpha- and interleukin 12-expressing RGD fiber-mutant Ads exhibited more effective tumor regression than the Ad expressing each alone. These results suggested that the fiber-mutant for altering Ad-tropism is a very potent technology for advancing gene therapy for melanoma.
Okada
Yuka
Y
Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Kyuban-cho, Koshien, Nishinomiya, Hyogo 663-8179, Japan.
Okada
Naoki
N
Nakagawa
Shinsaku
S
Mizuguchi
Hiroyuki
H
Kanehira
Makiko
M
Nishino
Naoko
N
Takahashi
Koichi
K
Mizuno
Nobuyasu
N
Hayakawa
Takao
T
Mayumi
Tadanori
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002213:Capsid / Q000235:genetics*; D036022:Capsid Proteins; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics*; D011991:Receptors, Virus / Q000032:analysis; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000494:pharmacology
D000956:Antigens, Viral; D000970:Antineoplastic Agents; D036022:Capsid Proteins; D009842:Oligopeptides; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; C018315:hexon capsid protein, Adenovirus; C047981:arginyl-glycyl-aspartic acid; D008156:Luciferases