title: Effectiveness and preclinical safety profile of doxycycline to be used "off-label" to induce therapeutic transgene expression in a phase I clinical trial for glioma.
abstract: Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al., 2010, 2012). In the present article, we investigated the efficacy and safety of the "off-label" use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX-inducible Flt3L expression in male Lewis rats was assessed using DOX doses of 30.8 mg/kg/day (low-DOX) or 46.2 mg/kg/day (high-DOX), which are allometrically equivalent (Voisin et al., 1990) to the human doses that are recommended for the treatment of infections: 200 or 300 mg/day. Naïve rats were intracranially injected with 1×10(9) viral particles of HC-Ad-TetOn-Flt3L, and expression of the therapeutic transgene, that is, Flt3L, was assessed using immunohistochemistry in brain sections after 2 weeks of DOX administration via oral gavage. The results show robust expression of Flt3L in the rat brain parenchyma in areas near the injection site in both the low-DOX and the high-DOX groups, suggesting that Flt3L will be expressed in human glioma patients at a DOX dose of 200 or 300 mg/day. These doses have been approved by the U.S. Food and Drug Administration to treat infections in humans and would thus be considered safe for an off-label use to treat GBM patients undergoing HC-Ad-mediated gene therapy in a phase I clinical trial.
authors.affiliation: 1 Department of Neurosurgery, The University of Michigan School of Medicine , Ann Arbor, MI 48109.
authors.forename: Nathan
authors.initials: N
authors.lastname: VanderVeen
authors.forename: Christopher
authors.initials: C
authors.lastname: Paran
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krasinkiewicz
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Shawn
authors.initials: S
authors.lastname: Hervey-Jumper
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D017321:Clinical Trials, Phase I as Topic; D004318:Doxycycline / Q000494:pharmacology / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy; D005909:Glioblastoma / Q000628:therapy*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D019076:Transgenes / Q000187:drug effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051941:fms-Like Tyrosine Kinase 3; D004318:Doxycycline