Interstitial Infusion of Carmustine in the Rat Brain Stem with Systemic Administration of O-benzylguanine

Abstract

Interstitial infusion of carmustine (BCNU) into the rat brain stem in conjunction with systemic administration of O6-benzylguanine (O6-BG) was performed in an effort to assess clinical tolerance. A total of 12 rats underwent stereotactic cannula placement into the pontine segment of the brain stem. Six of the rats underwent a 24-h infusion of BCNU (Volume of infusion [Vi] 200 microl) at its maximal concentrated dose (3.3 mg/ml) in 5% dextrose water. Six additional rats underwent 24-h infusion of BCNU preceded by an intraperitoneal injection of O6-BG at a dose of 50 mg/kg. Serial neurological examinations were performed on all animals. Histologic analyses were performed immediately or 2 weeks following sacrifice. Postoperatively, there were no neurological changes in any of the animals. Postmortem histological examination of the brains showed small pontine cavitary lesions (ranging from 20 to 250 microm) containing variable numbers of macrophages or neutrophils consistent with an inflammatory response. No changes beyond these findings indicated any histological evidence of injury. These finding were limited only to the cannula site and no changes beyond region of the cannula tract were found. These findings indicate that interstitial infusion of BCNU into the brain stem in conjunction with systemic administration of O6-BG is safe in a small animal and may serve as a potential investigative strategy for children with diffuse pontine gliomas.

The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model

“…One possible candidate is bevacizumab, as it has already been used for systemic therapy studies in glioma patients with promising results [27]. Another option is the combination of temozolomide with resistance modifiers such as O6-benzyl-guanine, INF-beta, and MGMTsiRNA [15,19,21,23].…”

Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies

“…20 Furthermore, studies have shown that local perfusion of the rat brainstem with chemotherapeutic agents, such as BCNU, carboplatin, and gemcitabine, is safe. 25,103 Distribution studies with CED have demonstrated that carboplatin can reach therapeutic levels in the brainstem, although it was shown that the drug diffused up to 4 mm around the tip of the cannula. Thus, larger tumors may need the placement of more than 1 cannula.…”

Interstitial Infusion of Glioma-Targeted Recombinant Immunotoxin 8H9scFv-PE38

“…The surgical procedure is performed as previously described (8, 17, 21). The animal is anesthetized by inhalational isoflurane and placed in a stereotactic frame (Kopf Instruments, California).…”