title: Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma.
abstract: OBJECTIVE
  Over the past several years, there has been increasing interest in combining angiogenesis inhibitors with radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma. Although the US FDA approved bevacizumab for the treatment of glioblastoma in 2009, the European Medicines Agency rejected its use due to its questionable impact on patient survival. One factor contributing to the failure of angiogenesis inhibitors to increase overall patient survival may be their inability to cross the blood-brain barrier. Here the authors examined in a 9L glioma model whether intracranial polymer-based delivery of the angiogenesis inhibitor minocycline potentiates the effects of both radiotherapy and temozolomide chemotherapy in increasing median survival. The authors also investigated whether the relative timing of minocycline polymer implantation with respect to radiotherapy affects the efficacy of radiotherapy.
  
  
  METHODS
  Minocycline was incorporated into the biodegradable polymer polyanhydride poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]) (CPP:SA) at a ratio of 50:50 by weight. Female Fischer 344 rats were implanted with 9L glioma on Day 0. The minocycline polymer was then implanted on either Day 3 or Day 5 posttumor implantation. Cohorts of rats were exposed to 20 Gy focal radiation on Day 5 or were administered oral temozolomide (50 mg/kg daily) on Days 5-9.
  
  
  RESULTS
  Both minocycline polymer implantations on Days 3 and 5 increased survival from 14 days to 19 days (p < 0.001 vs control). Treatment with a combination of both minocycline polymer and radiotherapy on Day 5 resulted in a 139% increase in median survival compared with treatment with radiotherapy alone (p < 0.005). There was not a statistically significant difference in median survival between the group that received minocycline implanted on the same day as radiotherapy and the group that received minocycline polymer 2 days prior to radiotherapy. Lastly, treatment with a combination of minocycline polymer with oral temozolomide resulted in a 38% extension of median survival compared with treatment of oral temozolomide alone (p < 0.001).
  
  
  CONCLUSIONS
  These results show that minocycline delivered locally potentiates the effects of both radiotherapy and oral temozolomide in increasing median survival in a rodent glioma model. More generally, these results suggest that traditional therapy in combination with local, as opposed to systemic, delivery of angiogenesis inhibitors may be able to increase median survival for patients with glioblastoma.
authors.affiliation: Departments of Neurosurgery.
authors.forename: Hansen
authors.initials: H
authors.lastname: Bow
authors.forename: Lee S
authors.initials: LS
authors.lastname: Hwang
authors.forename: Noam
authors.initials: N
authors.lastname: Schildhaus
authors.forename: Joanna
authors.initials: J
authors.lastname: Xing
authors.forename: Luke
authors.initials: L
authors.lastname: Murray
authors.forename: Quinn
authors.initials: Q
authors.lastname: Salditch
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jon
authors.initials: J
authors.lastname: Weingart
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D018316:Gliosarcoma / Q000628:therapy*; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D011108:Polymers / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D000077204:Temozolomide
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D011108:Polymers; D003606:Dacarbazine; D008911:Minocycline; D000077204:Temozolomide