title: Cytotoxicity of aphidicolin and its derivatives against neuroblastoma cells in vitro: synergism with doxorubicin and vincristine.
abstract: Disseminated neuroblastoma diseases are still indicated by a poor outcome despite treatment regimens including radiation therapy and high-dose chemotherapy with stem cell rescue. Therefore, new substances and treatment regimens are of interest. Aphidicolin (APH), a tetracyclic diterpene antibiotic produced by Cephalosporium aphidicola, has a specific toxicity for neuroblastoma cells. Furthermore, it was shown to enhance the effects of X-ray radiation and chemotherapy on malignant cells. To find new substances, 20 APH derivatives were tested for their anti-neuroblastoma efficacy in vitro in UKF-NB-2 cells. Five derivatives had antitumoral activity in neuroblastoma cells. A relationship between the structure and the antitumoral efficacy showed that the hydroxyl groups at C-3 and C-18 are essential for the antitumoral effects. Furthermore, antitumoral effects of APH in combination with doxorubicin and vincristine, both part of commonly used treatment regimens for disseminated neuroblastoma diseases, were tested in the neuroblastoma cell line UKF-NB-2. APH was found to act synergistically with vincristine and synergistically to additive with doxorubicin depending on the molecular ratio of the substances in combination. This may offer the chance to use APH and its derivatives as additional tools in the treatment of neuroblastomas.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Michaelis
authors.forename: J U
authors.initials: JU
authors.lastname: Vogel
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
authors.forename: K
authors.initials: K
authors.lastname: Langer
authors.forename: J
authors.initials: J
authors.lastname: Kreuter
authors.forename: D
authors.initials: D
authors.lastname: Schwabe
authors.forename: P H
authors.initials: PH
authors.lastname: Driever
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016590:Aphidicolin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D016590:Aphidicolin; D014750:Vincristine; D004317:Doxorubicin; C022616:thiazolyl blue