title: Gene therapy with secretory leukoprotease inhibitor promoter-controlled replication-competent adenovirus for non-small cell lung cancer.
abstract: Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLCs), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPI.E1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the cytomegalovirus (CMV) promoter that can selectively replicate only in NSCLC cells. Infection with AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a >100-fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24 cells). In contrast, neither E1A protein nor replication was detected in non-SLPI-producing HepG2 cells. Treatment with AdSLPI.E1AdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose-dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared with controls (A549, 57%, P < 0.02; H358, 67%, P < 0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMV.NK4 encoding NK4 protein, which has strong antiangiogenic activity. E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMV.NK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted in a more striking reduction of tumor growth compared with single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMV.NK4 may be a more effective gene therapy for NSCLC.
authors.affiliation: Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Aobaku Sendai, Japan. maemondo@idac.tohoku.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Saijo
authors.forename: Ko
authors.initials: K
authors.lastname: Narumi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Usui
authors.forename: Ryushi
authors.initials: R
authors.lastname: Tazawa
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Niitsu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000628:therapy* / Q000821:virology; D002455:Cell Division / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics*; D053481:Secretory Leukocyte Peptidase Inhibitor; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse