A Role for Altered Microtubule Polymer Levels in Vincristine Resistance of Childhood Acute Lymphoblastic Leukemia Xenografts (original) (raw)
Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY
, Natalia L. M. Liem, Michael A. Schmid, Nicole M. Verrills, Rachael A. Papa, Glenn M. Marshall, Karen L. MacKenzie, Maria Kavallaris and Richard B. Lock
Journal of Pharmacology and Experimental Therapeutics February 2008, 324 (2) 434-442; DOI: https://doi.org/10.1124/jpet.107.128926
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.
Footnotes
This work was supported by the Children's Cancer Institute Australia for Medical Research, grants from The Cancer Council New South Wales (to R.B.L. and K.L.M.), and the Leukemia Foundation Australia (M.K. and R.B.L.). M.K. was supported by a National Health and Medical Research Council RD Wright Career Development Award. K.L.M. was supported by a New South Wales Cancer Institute Career Development and Support Fellowship. The microarray analysis of gene expression data was provided by the Pediatric Preclinical Testing Program, which is supported by NO1-CM-42216 from the National Cancer Institute.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.128926.
ABBREVIATIONS: ALL, acute lymphoblastic leukemia; ABC, ATP-binding cassette; CEM, CCRF-CEM; QBSF, Quality Biological Serum Free; RPMI, Roswell Park Memorial Institute; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; PI, propidium iodide; calcein-AM, calcein-acetoxymethyl ester; MS-5, murine bone marrow stromal cell line; VCR, vincristine; WT, wild type; MK571, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid, sodium salt.
↵
The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.- Received July 19, 2007.
- Accepted November 5, 2007.
The American Society for Pharmacology and Experimental Therapeutics
Log in using your username and password
Purchase access
You may purchase access to this article. This will require you to create an account if you don't already have one.