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Targeted anti-mitotic therapies: can we improve on tubulin agents?

Nature Reviews Cancer volume 7, pages 107–117 (2007)Cite this article

Key Points

  • Anti-mitotic therapies that target tubulin are effective and widely used in treating cancer, but they have limitations related to the role of tubulin in the cytoskeleton of normal cells.

  • New compounds that inhibit new targets with specific functions in mitosis have now been identified, and show promising anti-tumour activity in preclinical model systems.

  • Early clinical studies have begun to show the pharmacodynamic activities of these new compounds in cancer patients.

  • These new mitotic inhibitors are very effective at preventing the proliferation of most tumour cells in vitro, but the subsequent cellular response to cell-cycle arrest is quite varied and includes apoptosis, mitotic catastrophe, mitotic slippage, senescence and reversible mitotic arrest depending on what cell line and/or inhibitor is studied.

  • At present, the genetic or biochemical factors that define how a particular tumour cell will respond to mitotic injuries are poorly understood, but will be very important in helping to identify which patients will be the best candidates for treatment with these new agents.

Abstract

The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.

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Figure 1: The phases of mitosis.
Figure 2: The mitotic checkpoint.

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Acknowledgements

We would like to thank K. Wood, J. Sabry and L. Sauermelch for helpful comments on the manuscript

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Authors and Affiliations

  1. Departments of Biology and Discovery Medicine, GlaxoSmithKline, Oncology Center of Excellence in Drug Discovery, Collegeville, Pennsylvania, USA

    Jeffrey R. Jackson, Denis R. Patrick & Mohammed M. Dar

  2. Merck and Co, Oncology Franchise, Upper Gwynned, Pennsylvania, USA

    Pearl S. Huang

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Correspondence to Jeffrey R. Jackson.

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Glossary

Pharmacodynamic markers

A molecular marker of drug response that can be measured in patients receiving the drug. The marker should be a direct measure of modulation of the drug target and be able to show quantitative changes in response to dose.

Monopolar spindle

A mitotic spindle in which the centrosomes are unseparated. A monopolar spindle is incapable of separating the sister chromatids because the spindle poles are not oriented on opposite sides of the chromosomes.

Spindle tension

In a properly functioning mitotic spindle, the microtubules that connect the chromosomes to the centrosomes are under tension. This tension, which creates a pulling force toward the centrosome, can be created by a poleward flux of tubulin within the microtubule, as well as kinesin and dynein motor proteins.

Bi-orientation

This describes chromosomes that have microtubule attatchments to both spindle poles.

Pharmacodynamic

Measurable physiological changes that occur in response to pharmacological modulation.

Neuropathy

A pathological state in which the normal function of the peripheral nervous system is perturbed. In the case of tubulin-binding drugs, this typically manifests as the inhibition of sensory neurons resulting in tingling and/or loss of feeling.

IC50

The concentration of a an inhibitor that is required for 50% inhibition of its target in vitro.

Immediate early genes

Genes whose expression is induced rapidly by growth factor stimulation.

Mitotic slippage

When a cell exits from mitosis without successfully separating the chromosomes or undergoing cytokinesis it is said to have undergone mitotic slippage. Essentially, such a cell has slipped out of mitosis and entered a G1like cell-cycle state but it now has double the chromosome number that it should have in G1.

Endoreduplication

This occurs after a cell undergoes mitotic slippage (having not divided), and then proceeds through the G1 phase with 4N DNA content and enters S phase to replicate its DNA again.

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Jackson, J., Patrick, D., Dar, M. et al. Targeted anti-mitotic therapies: can we improve on tubulin agents?. Nat Rev Cancer 7, 107–117 (2007). https://doi.org/10.1038/nrc2049

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