© Copyright 2008 by the Society for Neuro-Oncology
Received March 13, 2008
Accepted August 12, 2008
Basic and Translational Investigations
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Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases
Jens Hoffmann 1*,
Iduna Fichtner 2,
Margit Lemm 2,
Philip Lienau 3,
Holger Hess-Stumpp 3,
Andrea Rotgeri 3,
Birte Hofmann 3,
Ulrich Klar 3
1 Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse 172–178, 13342 Berlin, Germany
2 Max Delbrück Center for Molecular Medicine, Berlin, Germany
3 Bayer Schering Pharma AG, TRG Oncology, Berlin, Germany
* To whom correspondence should be addressed. E-mail: jens.hoffmann{at}bayerhealthcare.com.
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Abstract |
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The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in human orthotopic models of primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5–10 mg/kg, paclitaxel 8–12.5 mg/kg (or temozolomide 100 mg/kg), or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 human glioblastoma models, while paclitaxel showed a limited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastases models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.
Key Words:
blood-brain barrier, brain tumor models, sagopilone
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