title: Pulsed versus conventional radiation therapy in combination with temozolomide in a murine orthotopic model of glioblastoma multiforme.
abstract: OBJECTIVE
  To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model.
  
  
  METHODS
  Orthotopic U87MG hGBM tumors were established in Nu-Foxn1(nu) mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry.
  
  
  RESULTS
  Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ.
  
  
  CONCLUSIONS
  PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.
authors.affiliation: Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Lee
authors.forename: John L
authors.initials: JL
authors.lastname: Chunta
authors.forename: Sean S
authors.initials: SS
authors.lastname: Park
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Martinez
authors.forename: Inga S
authors.initials: IS
authors.lastname: Grills
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Krueger
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
authors.forename: Brian
authors.initials: B
authors.lastname: Marples
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D016371:Cranial Irradiation / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019583:Dose Fractionation, Radiation; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging / Q000379:methods; D049268:Positron-Emission Tomography; D011897:Random Allocation; D000077204:Temozolomide; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide