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

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 -