title: Simultaneous Administration of Statins and Pioglitazone Limits Tumor Growth in a Rat Model of Malignant Glioma.
abstract: Statins are cholesterol reducers with considerable dose-dependent effect against glioma cells. The apoptotic effect could be increased by combining statins or by adding pioglitazone (PGZ). The last one is an anti-diabetic drug, an agonist of the peroxisome proliferator-activated receptor-gamma (PPARG). We used an animal model to test the effect of such combination in vivo and we investigated the changes on immunological processes.
  
  
  
  Thirty-three rats (F344/DuCrl) were anesthetized and glioblastoma (F98) cells were implanted stereotactically. Animals were randomized into four groups: i) control (N=9); ii) intraperitoneal injection of PGZ 10 mg/kg/day (N=8); iii) oral administration of atorvastatin (ATVS) 40 mg/kg and lovastatin (LVS) 50 mg/kg (N=8); iv) oral administration of ATVS 40 mg/kg, LVS 50 mg/kg and PGZ 5 mg/kg (N=8). Treatment was started at 3rd postoperative day and continued for 14 days. The animals were followed-up for 30 days after start of therapy. Survival time, tumor volume, proliferation rate, counts of peripheral and tumor infiltrating leukocytes were compared.
  
  
  
  No difference of survival time or incidence of neurological deficits was observed. The combination of statins with PGZ led to a significant reduction in tumor volume by approximately 40% (p<0.05), statins combination was less effective and PGZ alone did not affect tumor volume. The groups treated with statins displayed significantly lower counts of peripheral CD3+, CD4+and CD8+T-cells and lower tumor associated CD68-positive cells (p<0.01, in respect to controls or PGZ alone). The proliferation rate was not statistically different. No relevant toxic effects were observed.
  
  
  
  Statins and PGZ are well-tolerated in rats and produced a significant tumor reduction, while an impact on neurological deficits or survival improvement could not be demonstrated. The reduction of infiltrating macrophages by using statins and PGZ should be further studied.
authors.affiliation: Neurological Clinic, Julius-Maximilian-University, Wuerzburg, Germany tapia_j@ukw.de.|Neurosurgical Clinic, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jorge Humberto
authors.initials: JH
authors.lastname: Tapia-Pérez
authors.affiliation: Neurosurgical Clinic, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Preininger
authors.affiliation: Neuropathological Institute, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Kirches
authors.affiliation: Institute for Molecular und Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Reinhold
authors.affiliation: Neurosurgical Clinic, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Butzmann
authors.affiliation: Neuropsychological Institute, Leibniz Institute, Magdeburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Prilloff
authors.affiliation: Neuropathological Institute, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.affiliation: Neurosurgical Clinic, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D005910:Glioma / Q000473:pathology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D000077205:Pioglitazone; D051381:Rats; D011916:Rats, Inbred F344; D045162:Thiazolidinediones / Q000008:administration & dosage*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Glioblastoma; macrophages; statin; thiazolidinediones