title: Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma.
abstract: Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.
authors.affiliation: Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Frazier
authors.forename: Paul P
authors.initials: PP
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Case
authors.forename: Betty M
authors.initials: BM
authors.lastname: Tyler
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pradilla
authors.forename: Jon D
authors.initials: JD
authors.lastname: Weingart
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D002330:Carmustine / Q000008:administration & dosage*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D018316:Gliosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D008911:Minocycline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D018906:Antineoplastic Agents, Alkylating; D003692:Delayed-Action Preparations; D008911:Minocycline; D002330:Carmustine