The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells.

Abstract

Concurrent radiochemotherapy for medulloblastoma includes the microtubule disrupting agent vincristine; however, vincristine alone or as part of a combined treatment regimen is highly toxic. A major goal is therefore to replace vincristine with novel potent chemotherapeutic agents-in particular, with microtubule stabilizing and destabilizing compounds-with a larger therapeutic window. Here, we investigated the antiproliferative, cytotoxic and radiosensitizing effect of patupilone (epothilone B [EPO906]), a novel, non-taxane-related and nonneurotoxic microtubule-stabilizing agent in human medulloblastoma cell lines. The antiproliferative and cytotoxic effects of patupilone alone and in combination with ionizing radiation was determined in the 3 representative human medulloblastoma cell lines D341Med, D425Med, and DAOY. Patupilone alone effectively reduced the proliferative activity and clonogenicity of all medulloblastoma cell lines tested at picomolar concentrations (50-200 pM) and resulted in an at least additive anticlonogenic effect in combination with clinically relevant doses of ionizing radiation (2 or 5 Gy). Cell-cycle analysis revealed a sequential G2-M arrest and sub-G1 accumulation in a dose- and treatment-dependent manner after exposure to patupilone. In tumor xenografts derived from D425Med cells, a minimal treatment regimen with patupilone and fractionated irradiation (1 × 2 mg/kg plus 3 × 3 Gy) resulted in an extended tumor growth delay for the 2 single treatment modalities alone and a supra-additive treatment response for the combined treatment modality, with complete tumor regressions. These results demonstrate the potent efficacy of patupilone against medulloblastoma cell lines and indicate that patupilone represents a promising candidate to replace vincristine as part of a combined treatment strategy with ionizing radiation.

• Authors: Christoph Oehler, André O von Bueren, Polina Furmanova, Angela Broggini-Tenzer, Katrin Orlowski, Stefan Rutkowski, Karl Frei, Michael A Grotzer, Martin Pruschy
• Journal: Neuro-oncology (Neuro Oncol) Vol. 13 Issue 9 Pg. 1000-10 (Sep 2011) ISSN: 1523-5866 [Electronic] England
• PMID: 21743064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Epothilones
• Radiation-Sensitizing Agents
• TP53 protein, human
• Tumor Suppressor Protein p53
• Caspase 3
• epothilone B

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cerebellar Neoplasms (genetics, pathology, therapy)
• Chemoradiotherapy
• Epothilones (therapeutic use)
• Humans
• Immunoenzyme Techniques
• Medulloblastoma (genetics, pathology, therapy)
• Mice
• Mice, Nude
• Microtubules (drug effects)
• Mutation (genetics)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (therapeutic use)
• Survival Rate
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays