The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells.
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The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells. / Oehler, Christoph; von Bueren, André; André, O; Furmanova, Polina; Broggini-Tenzer, Angela; Rutkowski, Stefan; Rutkowski, Stefan; Frei, Karl; Grotzer, Michael A; Pruschy, Martin.
in: NEURO-ONCOLOGY, Jahrgang 13, Nr. 9, 9, 2011, S. 1000-1010.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells.
AU - Oehler, Christoph
AU - von Bueren, André
AU - André, O
AU - Furmanova, Polina
AU - Broggini-Tenzer, Angela
AU - Rutkowski, Stefan
AU - Rutkowski, Stefan
AU - Frei, Karl
AU - Grotzer, Michael A
AU - Pruschy, Martin
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Survival Rate
KW - Mice
KW - Cell Line, Tumor
KW - Blotting, Western
KW - Immunoenzyme Techniques
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Mutation/genetics
KW - Mice, Nude
KW - Xenograft Model Antitumor Assays
KW - Antineoplastic Agents/therapeutic use
KW - Caspase 3/metabolism
KW - Cell Cycle/drug effects
KW - Cerebellar Neoplasms/genetics/pathology/therapy
KW - Chemoradiotherapy
KW - Epothilones/therapeutic use
KW - Medulloblastoma/genetics/pathology/therapy
KW - Microtubules/drug effects
KW - Radiation, Ionizing
KW - Radiation-Sensitizing Agents/therapeutic use
KW - Tumor Suppressor Protein p53/genetics
KW - Animals
KW - Humans
KW - Survival Rate
KW - Mice
KW - Cell Line, Tumor
KW - Blotting, Western
KW - Immunoenzyme Techniques
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Mutation/genetics
KW - Mice, Nude
KW - Xenograft Model Antitumor Assays
KW - Antineoplastic Agents/therapeutic use
KW - Caspase 3/metabolism
KW - Cell Cycle/drug effects
KW - Cerebellar Neoplasms/genetics/pathology/therapy
KW - Chemoradiotherapy
KW - Epothilones/therapeutic use
KW - Medulloblastoma/genetics/pathology/therapy
KW - Microtubules/drug effects
KW - Radiation, Ionizing
KW - Radiation-Sensitizing Agents/therapeutic use
KW - Tumor Suppressor Protein p53/genetics
M3 - SCORING: Journal article
VL - 13
SP - 1000
EP - 1010
JO - NEURO-ONCOLOGY
JF - NEURO-ONCOLOGY
SN - 1522-8517
IS - 9
M1 - 9
ER -