A role for altered microtubule polymer levels in vincristine resistance of childhood acute lymphoblastic leukemia xenografts.

Abstract

The microtubule-depolymerizing drug, vincristine, is effective in the treatment of acute lymphoblastic leukemia (ALL). Although vincristine resistance mechanisms have been extensively characterized in cell lines, their clinical relevance is poorly understood. The aim of the current study was to define clinically relevant mechanisms of vincristine resistance in a panel of childhood ALL xenografts established in immune-deficient (nonobese diabetic/severe combined immunodeficient) mice. We also studied two independent xenograft sublines that were selected by in vivo vincristine exposure. In vitro vincristine sensitivity determined by a stromal coculture, murine bone marrow stromal cell line (MS-5), assay, but not methyl-thiazolyl-tetrazolium metabolic activity assay, significantly correlated (P = 0.05) with the length of the patients' first remission. Investigations into mechanisms of resistance revealed no association with steady-state vincristine accumulation or increased activity and/or expression of ATP-binding cassette transporters, although increased intracellular levels of polymerized tubulin significantly correlated with resistance (r = 0.85; P = 0.0019). Two xenograft sublines selected by in vivo vincristine exposure exhibited a 2-fold increase in polymerized tubulin levels compared with the parental subline (P < 0.05), reflecting their in vivo vincristine resistance. In this study, a vincristine-resistant xenograft with high levels of polymerized tubulin was relatively sensitive to the microtubule-polymerizing drug paclitaxel. These results indicate that the balance between polymerized and nonpolymerized tubulin may be an important determinant of response to Vinca alkaloid-based chemotherapy regimens in childhood ALL.

• Authors: Vivienna Ong, Natalia L M Liem, Michael A Schmid, Nicole M Verrills, Rachael A Papa, Glenn M Marshall, Karen L Mackenzie, Maria Kavallaris, Richard B Lock
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 324 Issue 2 Pg. 434-42 (Feb 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 17986648 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Polymers
• Vincristine

Topics

• Animals
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, physiology)
• Humans
• Mice
• Microtubules (drug effects, metabolism)
• Polymers (metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Vincristine (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays (methods)