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¹ Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia and ² Australian Proteome Analysis Facility, Macquarie University, Sydney, New South Wales, Australia

Requests for reprints: Maria Kavallaris, Children's Cancer Institute Australia for Medical Research, High Street, P.O. Box 81, Randwick, New South Wales 2031, Australia. Phone: 61-2-9382-1823; Fax: 61-2-9382-1850. E-mail: m.kavallaris{at}unsw.edu.au

Advanced stage neuroblastoma has a poor clinical outcome and microtubule-destabilizing agents, such as the Vinca alkaloids, are an important component in the treatment of this childhood cancer. Vinca alkaloids bind to ß-tubulin on the /ß-tubulin heterodimer and disrupt microtubule dynamics, leading to cell death. To date, studies examining the contribution of microtubules and associated proteins to the efficacy of microtubule-destabilizing agents in neuroblastoma have been limited. In this study, BE(2)-C neuroblastoma cells previously selected for resistance to either vincristine (BE/VCR10) or colchicine (BE/CHCb0.2) were found to display significant decreases in neuronal-specific class III ß-tubulin. Interestingly, vincristine-selected cells exhibited increased levels of polymerized tubulin that were not due to -tubulin and class I, II, or III ß-tubulin mutations. Expression levels of the microtubule-depolymerizing protein stathmin were significantly increased in BE/VCR10 cells. In contrast, levels of MAP2a and MAP2b were relatively unaltered. A marked decrease in the neuronal protein, MAP2c, was identified in the vincristine-selected cells and, to a lesser extent, in the colchicine-selected cells. This is the first report describing specific microtubule alterations in neuroblastoma cells resistant to tubulin-targeted agents. The results indicate a need to identify the factors responsible for resistance to tubulin-targeted agents in neuroblastoma so that improved and novel treatment strategies can be developed for this drug refractory disease.

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Received 2/ 5/04; revised 6/14/04; accepted 7/ 9/04.