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Mitosis is not a key target of microtubule agents in patient tumors

Nature Reviews Clinical Oncology volume 8, pages 244–250 (2011)Cite this article

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Abstract

Mitosis-specific agents have, to date, not been clinically successful. By contrast, microtubule-targeting agents (MTAs) have a long record of success, usually attributed to the induction of mitotic arrest. Indeed, it was this success that led to the search for mitosis-specific inhibitors. We believe the clinical disappointment of mitosis-specific inhibitors stands as evidence that MTAs have been successful not only by interfering with mitosis but, more importantly, by disrupting essential interphase cellular mechanisms. In this Perspective we will review literature that supports a paradigm shift in how we think about one of our most widely used classes of chemotherapeutics—MTAs. We believe that the steady presence and constant physiological role of microtubules are responsible for the overall success of MTAs. While mitosis-specific inhibitors are effective on only a small fraction of the tumor mass (dividing cells), MTAs target tubulin, a protein that has crucial roles in both mitotic and non-mitotic cells.

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Figure 1: Cellular organization depicting structures and proteins involved in cell division.
Figure 2: The localization of aurora kinase A (red), aurora kinase B (orange), and polo-like kinases (green) during the different stages of mitosis.
Figure 3: Microtubule-targeting agents induce mitotic arrest and abnormal spindle in preclinical models.
Figure 4: Biopsies obtained from four patients with metastatic breast cancer after treatment with the microtubule-stabilizing agent, ixabepilone (6 mg/m2 per day for 5 days).

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  • 04 March 2011

    In the version of this article initially published online, the legend for Figure 3 should have contained the sentence 'Permission for parts c and d obtained from Elsevier © Mabjeesh, N. J. et al. Cancer Cell 3, 363–375 (2003)'. This has now been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

The authors would like to thank S. X.Yung for immunohistochemical staining of breast cancer samples. This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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Authors and Affiliations

  1. National Cancer Institute, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, 20892, MD, USA

    Edina Komlodi-Pasztor, Julia Wilkerson & Tito Fojo

  2. National Institute of Child Health and Human Development, National Institutes of Health, Building 9, 9 Memorial Drive, Bethesda, 20892, MD, USA

    Dan Sackett

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Contributions

All authors contributed to researching the data for the article. E. Komlodi-Pasztor, D. Sackett and T. Fojo made a substantial contribution to discussion of the content, writing the article and preparing it for submission.

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Correspondence to Edina Komlodi-Pasztor.

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Supplementary information

Supplementary Table 1

Targets of mitotic-kinase inhibitors (DOC 82 kb)

Supplementary Table 2

Lung cancer: tumor doubling times (DOC 66 kb)

Supplementary Table 3

Colon cancer: doubling time of serum CEA (DOC 49 kb)

Supplementary Table 4

Colon cancer: tumor doubling times (DOC 41 kb)

Supplementary Table 5

Hepatocellular carcinoma: tumor doubling times (DOC 65 kb)

Supplementary Table 6

Breast cancer: tumor doubling times (DOC 61 kb)

Supplementary Table 7

Prostate cancer: doubling time of serum PSA (DOC 68 kb)

Supplementary Table 8

Prostate cancer: tumor doubling times (DOC 37 kb)

Supplementary Table 9

Melanoma: tumor doubling times (DOC 45 kb)

Supplementary Table 10

Neutrophil cellularity and kinetics in humans (DOC 39 kb)

Supplementary Table 11

Partial list of proteins that traffic on or associate with microtubules (DOC 80 kb)

Supplementary Table 12

Agents that disrupt mitosis: limited activity to date (DOC 75 kb)

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Komlodi-Pasztor, E., Sackett, D., Wilkerson, J. et al. Mitosis is not a key target of microtubule agents in patient tumors. Nat Rev Clin Oncol 8, 244–250 (2011). https://doi.org/10.1038/nrclinonc.2010.228

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