title: Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario.
abstract: Suicide gene therapy mediated by mesenchymal stem cells with their ability to engraft into tumors makes these therapeutic stem cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we evaluated the therapeutic efficacy of human mesenchymal stem cells derived from bone marrow and from adipose tissue, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracerebral rat C6 glioblastoma in a simulated clinical therapeutic scenario. Intracerebrally grown glioblastoma was treated by resection and subsequently with single or repeated intracerebral inoculations of therapeutic stem cells followed by a continuous intracerebroventricular delivery of 5-fluorocytosine using an osmotic pump. Kaplan-Meier survival curves revealed that surgical resection of the tumor increased the survival time of the resected animals depending on the extent of surgical intervention. However, direct injections of therapeutic stem cells into the brain tissue surrounding the postoperative resection cavity led to a curative outcome in a significant number of treated animals. Moreover, the continuous supply of therapeutic stem cells into the brain with growing glioblastoma by osmotic pumps together with continuous prodrug delivery also proved to be therapeutically efficient. We assume that observed curative therapy of glioblastoma by stem cell-mediated prodrug gene therapy might be caused by the destruction of both tumor cells and the niche where glioblastoma initiating cells reside.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Laboratory of Molecular Oncology, Bratislava, Slovakia; St. Elisabeth Cancer Institute, Center for Cell Therapy and Regenerative Medicine, Bratislava, Slovakia.
authors.forename: Cestmir
authors.initials: C
authors.lastname: Altaner
authors.forename: Veronika
authors.initials: V
authors.lastname: Altanerova
authors.forename: Marina
authors.initials: M
authors.lastname: Cihova
authors.forename: Katarina
authors.initials: K
authors.lastname: Ondicova
authors.forename: Boris
authors.initials: B
authors.lastname: Rychly
authors.forename: Ladislav
authors.initials: L
authors.lastname: Baciak
authors.forename: Boris
authors.initials: B
authors.lastname: Mravec
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics*; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D010430:Pentosyltransferases / Q000235:genetics*; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000963:Antimetabolites; D011355:Prodrugs; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase
keywords: 5-fluorocytosine; CDy::UPRT; glioblastoma; suicide gene therapy; therapeutic stem cells