title: Improvement in the standard treatment for experimental glioma by fusing antibody Fc domain to endostatin.
abstract: OBJECTIVE
  Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods.
  
  
  METHODS
  Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect.
  
  
  RESULTS
  Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post-tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5-9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors.
  
  
  CONCLUSIONS
  Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.
authors.affiliation: Department of Neurosurgery, Oncology and Biomedical Engineering, School of Medicine, Hopkins University, Baltimore, Maryland, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.forename: Lee
authors.initials: L
authors.lastname: Hwang
authors.forename: Patti
authors.initials: P
authors.lastname: Zadnik
authors.forename: Bachchu
authors.initials: B
authors.lastname: Lal
authors.forename: Kashi
authors.initials: K
authors.lastname: Javaherian
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D043169:Endostatins / Q000494:pharmacology* / Q000633:toxicity; D018316:Gliosarcoma / Q000188:drug therapy* / Q000401:mortality; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D000077204:Temozolomide
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D043169:Endostatins; D007141:Immunoglobulin Fc Fragments; D003606:Dacarbazine; D000077204:Temozolomide