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Local Delivery of Minocycline and Systemic BCNU have Synergistic Activity in the Treatment of Intracranial Glioma

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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.

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Authors and Affiliations

  1. Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    James L. Frazier, Paul P. Wang, Daniel Case, Betty M. Tyler, Gustavo Pradilla, Jon D. Weingart & Henry Brem

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  1. James L. Frazier
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  2. Paul P. Wang
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  4. Betty M. Tyler
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Frazier, J.L., Wang, P.P., Case, D. et al. Local Delivery of Minocycline and Systemic BCNU have Synergistic Activity in the Treatment of Intracranial Glioma. J Neurooncol 64, 203–209 (2003). https://doi.org/10.1023/A:1025695423097

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