title: Inhibition of glioblastoma and enhancement of survival via the use of mibefradil in conjunction with radiosurgery.
abstract: OBJECTIVE
  The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery.
  
  
  METHODS
  Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor volumes were measured on MR images. Experimental Group 1 received 30 mg/kg of mibefradil intraperitoneally 3 times a day for 1 week starting on postoperative day (POD) 15; Group 2 received 8 Gy of cranial radiation via radiosurgery delivered on POD 15; Group 3 underwent radiosurgery on POD 15, followed by 1 week of mibefradil; and Group 4 received mibefradil on POD 15 for 1 week, followed by radiosurgery sometime from POD 15 to POD 22. Twenty-seven glioma-bearing rats were analyzed. Survival was compared between groups using Kaplan-Meier methodology.
  
  
  RESULTS
  Median survival in Groups 1, 2, 3, and 4 was 35, 31, 43, and 52 days, respectively (p = 0.036, log-rank test). Two animals in Group 4 survived to POD 60, which is twice the expected survival of untreated animals in this model. Analysis of variance and a post hoc test indicated no tumor volume differences on PODs 15 and 29. However, significant volume differences were found on POD 43; mean tumor volumes for Groups 1, 2, 3, and 4 were 250, 266, 167, and 34 mm(3), respectively (p = 0.046, ANOVA). A Cox proportional hazards regression test showed survival was associated with tumor volume on POD 29 (p = 0.001) rather than on POD 15 (p = 0.162). In vitro assays demonstrated an appreciable and dose-dependent increase in apoptosis between 2- and 7-μM concentrations of mibefradil.
  
  
  CONCLUSIONS
  Mibefradil response is schedule dependent and enhances survival and reduces glioblastoma when combined with ionizing radiation.
authors.affiliation: Department of Neurological Surgery, University of Virginia, Charlottesville, VA 22908, USA. jps2f@virginia.edu
authors.forename: Jason P
authors.initials: JP
authors.lastname: Sheehan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Xu
authors.forename: Britney
authors.initials: B
authors.lastname: Popp
authors.forename: Leigh
authors.initials: L
authors.lastname: Kowalski
authors.forename: David
authors.initials: D
authors.lastname: Schlesinger
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D008279:Magnetic Resonance Imaging; D020748:Mibefradil / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D016634:Radiosurgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D002121:Calcium Channel Blockers; D020748:Mibefradil