title: Model for concomitant microdialysis sampling of the pons and cerebral cortex in rhesus macaques (Macaca mulatta).
abstract: Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue compared with cortical brain tissue. To test this hypothesis, we developed a unique nonhuman primate model using microdialysis, a continuous in vivo extracellular sampling technique, to compare drug exposure concurrently in pontine tissue, cortical tissue, CSF, and plasma after intravenous administration of chemotherapeutic agents. The surgical coordinates and approach for microdialysis cannula-probe placement were determined in 5 adult male rhesus monkeys (Macaca mulatta) by using MRI. Microdialysis cannulas-probes were implanted stereotactically in the brain, retrodialysis was performed to measure relative recovery, and a 1-h intravenous infusion of temozolomide was administered. Continuous microdialysis samples were collected from the pons and cortex over 4 h with concurrent serial plasma and CSF samples. Postsurgical verification of microdialysis cannula-probe placement was obtained via MRI in 3 macaques and by gross pathology in all 5 animals. The MRI-determined coordinates and surgical methodologies resulted in accurate microdialysis probe placement in the pons and cortex in 4 of the 5 macaques. Histologic examination from these 4 animals revealed negligible tissue damage to the pontine and cortical tissue from microdialysis. One macaque was maintained for 8 wk and had no deficits attributed to the procedure. This animal model allows for the determination of differences in CNS penetration of chemotherapeutic agents in the pons, cortex, and CSF after systemic drug administration.
authors.affiliation: National Cancer Institute, Bethesda, Maryland, USA. mccullyc@mail.nih.gov.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: McCully
authors.forename: Devang
authors.initials: D
authors.lastname: Pastakia
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Thomas
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Steffen-Smith
authors.forename: Kadharbatcha
authors.initials: K
authors.lastname: Saleem
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Stuart
authors.initials: S
authors.lastname: Walbridge
authors.forename: Lauren
authors.initials: L
authors.lastname: Brinster
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis / Q000379:methods*; D023421:Models, Animal; D000077204:Temozolomide
chemical_list: D003606:Dacarbazine; D000077204:Temozolomide