title: Midkine promoter-based adenoviral suicide gene therapy to midkine-positive pediatric tumor.
abstract: OBJECTIVE
  Suicide gene therapy based on the delivery of the herpes simplex virus thymidine kinase gene combined with ganciclovir (HSV-tk/GCV) is a promising approach for cancer treatment. Adenoviral (Ad) vectors are useful gene delivery vehicles for this approach; however, because these agents possess a high natural tropism for the liver, systems must be designed to avoid potential hepatotoxicity induced by expression of the therapeutic gene in this organ. It has been reported that Wilms' tumors or neuroblastomas express a high level of midkine (MK), a heparin-binding growth factor. In addition, no MK expression is observed in mouse or human liver. The authors investigated the application of MK promoter-based adenoviral gene therapy for MK-positive tumors, especially Wilms' tumors or neuroblastomas, and have shown that the MK promoter retains its fidelity in the adenoviral context, having low activity in liver and high activity in MK-positive tumor cells. We present herein the efficacy of in vivo tumor regression as well as prevention of lethal hepatic toxicity by using the MK promoter in an Ad vector-based HSV-tk/GCV treatment approach.
  
  
  METHODS
  Ad vectors, AdMKTK or AdCMVTK, encoding HSV-tk under the control of the MK or cytomegalovirus promoters, respectively, were injected systemically into mice, then hepatotoxicity and survival was monitored after GCV administration. In concurrent studies, the therapeutic impact of AdMKTK/GCV versus AdCMVTK/GCV on subcutaneous G-401 Wilms' tumors in nude mice was assessed.
  
  
  RESULTS
  By day 8 of systemic viral treatment, 4 of 5 mice treated with AdCMVTK/GCV had died, whereas all mice treated with AdMKTK/GCV survived at least 10 days. In the subcutaneous tumor study, equivalent regression of tumor was seen in the group that received AdMKTK as the group that received AdCMVTK intratumoral injection.
  
  
  CONCLUSIONS
  These data indicate that the MK promoter-based adenoviral suicide gene therapy is a unique therapeutic candidate for MK-positive tumors, Wilms' tumors, or neuroblastomas, by virtue of its mild hepatotoxicity and high efficacy against MK-positive tumors.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Adachi
authors.forename: Shyuichiro
authors.initials: S
authors.lastname: Matsubara
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage*; D056486:Chemical and Drug Induced Liver Injury; D016207:Cytokines; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051379:Mice; D008819:Mice, Nude; D000078792:Midkine; D009447:Neuroblastoma / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000502:physiology; D018139:Simplexvirus / Q000737:chemistry / Q000235:genetics; D013936:Thymidine / Q000737:chemistry / Q000235:genetics; D009396:Wilms Tumor / Q000628:therapy*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D000078792:Midkine; D013936:Thymidine