Treatment of drug-resistant human neuroblastoma cells with cyclodextrin inclusion complexes of aphidicolin.

Treatment failure in most neuroblastoma (NB) patients is related to primary and/or acquired resistance to conventional chemotherapeutic agents. Aphidicolin (APH), a tetracyclic diterpene, exhibits specific cytotoxic action against NE cells. The purpose of this study was to compare antitumoral efficacy of APH in parental NE cell lines and cell subclones that exhibit drug resistance to vincristine (VCR), doxorubicin (DOX) and cisplatin. Due to poor solubility of APH in water, gamma -cyclodextrin (gamma -CD) inclusion complexes of APH were used for systemic treatment of xenotransplanted parental and VCR-resistant UKF-NB-3 tumours. APH and its gamma -CD inclusion complexes inhibited growth of parental and drug-resistant NE cells at equimolar doses in vitro. Growth of VCR-sensitive end -resistant NE tumors was inhibited at equal doses in a dose-dependent fashion in vivo. These results indicate that the specific cytotoxic activity of APH against NE cells in vitro and in vivo is independent of cellular mechanisms facilitating drug resistance to conventional chemotherapeutic drugs. Hence, taking into account our previous findings that APH acts synergistically with VCR and DOX, APH might be an additive tool for the therapy of Ha and is suitable for evaluation in clinical studies of NE treatment protocols. [(C) 2001 Lippincott Williams & Wilkins.].