Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth.
Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.
Watanabe
Masami
M
Department of Urology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan. masami5@cf6.so-net.ne.jp
Nasu
Yasutomo
Y
Kashiwakura
Yuji
Y
Kusumi
Norihiro
N
Tamayose
Kenji
K
Nagai
Atsushi
A
Sasano
Tetsuo
T
Shimada
Takashi
T
Daida
Hiroyuki
H
Kumon
Hiromi
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000628:therapy; D011467:Prostate / Q000098:blood supply / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D015843:Serpins / Q000235:genetics*; D019311:Staurosporine / Q000494:pharmacology; D015996:Survival Rate; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
C085344:SERPIN-B5; D015843:Serpins; D019311:Staurosporine