Cytotoxicity of aphidicolin and its derivatives against neuroblastoma cells in vitro: synergism with doxorubicin and vincristine

Disseminated neuroblastoma diseases are still indicated by a poor outcome d espite treatment regimens including radiation therapy and high-dose chemoth erapy with stem cell rescue. Therefore, new substances and treatment regime ns are of interest. Aphidicolin (APH), a tetracyclic diterpene antibiotic p roduced by Cephalosporium aphidicola, has a specific toxicity for neuroblas toma cells. Furthermore, it was shown to enhance the effects of X-ray radia tion and chemotherapy on malignant cells. To find new substances, 20 APH de rivatives were tested for their anti-neuroblastoma efficacy in vitro in UKF -NB-2 cells, Five derivatives had antitumoral activity in neuroblastoma cel ls. A relationship between the structure and the antitumoral efficacy showe d that the hydroxyl groups at C-3 and C-18 are essential for the antitumora l effects, Furthermore, antitumoral effects of APH in combination with doxo rubicin 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 sy nergistically 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 teals in the treatment of neuroblastomas. [( C) 2000 Lippincott Williams & Wilkins].