Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy.
OBJECTIVE
To determine the acute and long-term effects of a therapeutic dose of brain radiation in a primate model, the authors studied the clinical, laboratory, neuroimaging, molecular, and histological outcomes in rhesus monkeys that had received fractionated whole-brain radiation therapy (WBRT).


METHODS
Twelve 3-year-old male primates (Macaca mulatta) underwent fractionated WBRT (350 cGy for 5 days/week for 2 weeks, total dose 3500 cGy). Animals were followed clinically and with laboratory studies and serial magnetic resonance (MR) imaging. They were killed when they developed medical problems or neurological symptoms, lesions appeared on MR imaging, or at study completion. Gross, histological, and molecular analyses were then performed. Nine (82%) of 11 animals that underwent long-term follow up (> 2.5 years) developed neurological symptoms and/or enhancing lesions on MR imaging, which were defined as glioblastoma multiforme (GBM), 2.9 to 8.3 years after radiation therapy. The GBMs were categorized as either unifocal (three) or multifocal (six), and were located in the supratentorial (six), infratentorial (two), or both (one) cranial regions. Histological examination revealed distant, noncontiguous tumor invasion within the white matter of all nine animals harboring GBMs. Novel interspecies comparative genomic hybridization (three animals) uniformly showed deletions in the GBMs that corresponded to chromosome 9 in humans.


CONCLUSIONS
The high rate of GBM formation (82%) following a therapeutic dose of WBRT in nonhuman primates indicates that radioinduction of these neoplasms as a late complication of this therapy may occur more frequently than is currently recognized in human patients. The development of these tumors while monitoring the monkeys' conditions with clinical and serial MR imaging studies, and access to the tumor and the entire brain for histological and molecular analyses offers an opportunity to gather unique insights into the nature and development of GBMs.
Lonser
Russell R
RR
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Walbridge
Stuart
S
Vortmeyer
Alexander O
AO
Pack
Svetlana D
SD
Nguyen
Tung T
TT
Gogate
Nitin
N
Olson
Jeffery J
JJ
Akbasak
Aytac
A
Bobo
R Hunt
RH
Goffman
Thomas
T
Zhuang
Zhengping
Z
Oldfield
Edward H
EH
D000818:Animals; D001932:Brain Neoplasms / Q000209:etiology* / Q000473:pathology / Q000532:radiotherapy*; D004273:DNA, Neoplasm / Q000032:analysis; D004307:Dose-Response Relationship, Radiation; D004815:Epidermal Growth Factor / Q000235:genetics; D005909:Glioblastoma / Q000209:etiology* / Q000473:pathology / Q000532:radiotherapy*; D015848:Interleukin-5 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009693:Nucleic Acid Hybridization; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004273:DNA, Neoplasm; D015848:Interleukin-5; D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53; D004815:Epidermal Growth Factor