Improvement in the standard treatment for experimental glioma by fusing antibody Fc domain to endostatin

Document Type

Article

Abstract

OBJECT: 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.

Medical Subject Headings

Administration, Oral; Angiogenesis Inhibitors (pharmacology, toxicity); Animals; Antineoplastic Agents, Alkylating (pharmacology); Antineoplastic Combined Chemotherapy Protocols (pharmacology); Brain Neoplasms (drug therapy, mortality); Dacarbazine (analogs & derivatives, pharmacology); Disease Models, Animal; Drug Delivery Systems (methods); Endostatins (pharmacology, toxicity); Gliosarcoma (drug therapy, mortality); Immunoglobulin Fc Fragments (pharmacology, toxicity); Male; Rats; Rats, Inbred F344; Survival Analysis; Temozolomide

Publication Date

12-1-2011

Publication Title

Journal of neurosurgery

E-ISSN

1933-0693

Volume

115

Issue

6

First Page

1139

Last Page

46

PubMed ID

21923243

Digital Object Identifier (DOI)

10.3171/2011.8.JNS11125

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