Received for publication July 23, 2007.
Revised November 3, 2007.
Accepted for publication November 5, 2007.

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). While 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 (NOD/SCID) mice, as well as two independent xenograft sublines that were selected by in vivo vincristine exposure. In vitro vincristine sensitivity determined by a stromal co-culture (MS-5) assay, but not MTT metabolic activity assay, significantly correlated (P=0.05) with 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. Finally, 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 non-polymerized tubulin may be an important determinant of response to Vinca alkaloid-based chemotherapy regimens in childhood ALL.

Key words: Chemotherapy, Drug resistance, Leukemia, Tubulin, Vincristine, Xenografts