title: The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model.
abstract: OBJECTIVE
  Diffuse intrinsic brainstem gliomas are considered to be inoperable. We report our initial experience of temozolomide (TMZ) administration into brainstem by intracerebral (i.c.) microinfusion using a rat brainstem glioblastoma allograft model.
  
  
  METHODS
  Forty-eight Fischer 344 female rats were used. In a feasibility study, various doses of i.c.-TMZ (1-10 mg) were administered into the brainstem using AlzetTM pumps in order to evaluate survival rates and neurotoxicity. For tumor implantation, rats received an injection of 10(5) 9 L gliosarcoma cells. For local therapy, 5 days after inoculation, a total amount of 1 mg of TMZ or saline was administered into the brainstem at 1 μl/h over 7 days (n = 8/group). For systemic therapy, rats were treated with an orally administered maximum daily dose of 50 mg/kg TMZ for 5 consecutive days. Survival time and neurological deficit were recorded as outcome parameters.
  
  
  RESULTS
  In the neurotoxicity study, low dose TMZ (1 mg) was feasible to be administered into brainstem over 7 days without neurological deficit. Using high dose TMZ (5-10 mg), marked neurotoxic effect was observed. In the brainstem tumor study, survival was significantly prolonged in low dose i.c.-TMZ group compared to control rats (median survival 23.5 versus 29.5 days; p < 0.01). Systemic therapy with maximal oral-TMZ dose resulted in longer survival time compared to low dose i.c.-TMZ group (median survival 33.5 versus 29.5 days; p < 0.01).
  
  
  CONCLUSIONS
  i.c.-TMZ is feasible and effective against rat brainstem glioblastoma allograft. However, we could not show superior potential of i.c.-TMZ compared to oral-TMZ administration. Modification of TMZ infusion with systemic therapy warrants future investigations.
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. junyoshi@bri.niigata-u.ac.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshimura
authors.forename: I-Mei
authors.initials: IM
authors.lastname: Siu
authors.forename: Ulrich-W
authors.initials: UW
authors.lastname: Thomale
authors.forename: George I
authors.initials: GI
authors.lastname: Jallo
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D001933:Brain Stem / Q000187:drug effects* / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D057967:Infusions, Intraventricular; D008845:Microinjections / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate / Q000639:trends; D000077204:Temozolomide; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide