title: Targeted delivery of CYP2E1 recombinant adenovirus to malignant melanoma by bone marrow-derived mesenchymal stem cells as vehicles.
abstract: The aim of this study was to explore the effects of bone marrow-derived mesenchymal stem cells (BMSCs) as intermediate carriers on targeting of P450 gene recombinant adenovirus to malignant melanoma in vitro and in vivo. BMSCs were transduced with pAd5-CMV-CYP2E1 recombinant adenovirus. BMSC migration was detected by Transwell plates in vitro and by superparamagnetic iron oxide particles in vivo. Growth-inhibitory effect and apoptosis were determined by MTT and immunity fluorescence staining. Anticancer effects were examined by a human melanoma nude mouse model in vivo. BMSCs moved toward A375 cells in Transwell plates. Numerous superparamagnetic MSCs labeled with iron oxide were identified in the peripheral areas of the tumor, but were detected in primary organs by Prussian blue staining. BMSC-CYP2E1 cells mediated a bystander killing effect on CYP2E1-negative A375 cells during coculture (IC50 values for A375 cells cocultured with BMSC-EGFP and BMSC-CYP2E1 were 4.08 and 2.68 mmol/l, respectively). Intravenously injecting CYP2E1 recombinant adenovirus-loaded BMSCs in mice with established human melanoma managed to target the tumor site, and BMSCs with forced expression of CYP2E1 inhibited the growth of malignant cells in vivo by activating 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide. BMSCs may serve as a platform of P450 gene-directed enzyme prodrug therapy for the delivery of chemotherapeutic prodrugs to tumors.
authors.affiliation: aGuiZhou Province Laboratory of Hematological Disease Diagnostic & Treat Centre bGuiZhou Province Hemopoietic Stem Cell Transplantation Centre cDepartment of Hematology, Affiliated Hospital of Guiyang Medical College dDepartment of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical College, Guiyang, China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D003606:Dacarbazine / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019392:Cytochrome P-450 CYP2E1