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Experimental Therapeutics |
Children’s Cancer Institute Australia for Medical Research, Randwick, NSW, Australia 2031 [M. K., A. S. T., M. D. N., M. H.]; Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia 2109 [B. J. W.]; and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, 10461 [L. H., S. B. H.]
Vinca alkaloids are used extensively in the treatment of childhood acute lymphoblastic leukemia (ALL) and despite their usefulness, drug resistance remains a serious clinical problem. Vinca alkaloids bind to the ß-tubulin subunit of the 
/ß-tubulin heterodimer and inhibit polymerization of microtubules. Recent studies have implicated altered ß-tubulin isotype expression and mutations in resistance to microtubule-stabilizing agents. Microtubule-associated protein (MAP) MAP4 binds to and stabilizes microtubules, and increased expression is associated with decreased sensitivity to microtubule-depolymerizing agents. To address the significance of ß-tubulin and MAP4 alterations in childhood ALL, two CCRF-CEM-derived Vinca alkaloid resistant cell lines, VCR R (vincristine) and VLB100 (vinblastine), were examined. Decreased expression of class III ß-tubulin was detected in both VCR R and VLB100 cells. VCR R cells and to a lesser extent VLB100 cells expressed increased levels of MAP4 protein. Increased microtubule stability was observed in these VCR R cells as identified by the high levels of polymerized tubulin (45.6 ± 2.6%; P < 0.005) compared with CEM and VLB100 cells (24.7 ± 3.3% and 24.7 ± 2.5%, respectively). Expression was associated with a single MAP4 isoform in the polymerized microtubule fraction in CEM and VCR cells. In contrast, VLB100 cells expressed a lower molecular weight isoform in the polymerized fraction. Two-dimensional-PAGE and immunoblotting revealed marked posttranslational changes in class I ß-tubulin in VCR R cells not evident in CEM cells. Sequencing of the ß-tubulin (HM40) gene identified a point mutation in VCR R cells in nucleotide 843 (CTC
ATC; Leu240Ile) that was not present in CEM or VLB100 cells. This mutation resides in a region of ß-tubulin that lies in close proximity to the /ß tubulin interface. Multiple alterations related to normal microtubule function were identified in ALL cells selected for resistance to Vinca alkaloids, and these alterations may provide important insight into mechanisms mediating resistance to Vinca alkaloids.
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