Key Points
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Microtubule-binding agents are one of the oldest and most diverse family of anticancer agents. This family has recently been enriched with the approval of ixabepilone, vinflunine and cabazitaxel. Most approved and investigational agents are either natural or semi-synthetic compounds.
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These agents act primarily by reducing microtubule dynamics, inducing mitotic arrest and tumour cell death. They are therefore complementary to agents that target DNA or to targeted therapies such as tyrosine kinase inhibitors or monoclonal antibodies.
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Novel agents are being developed as vascular-disrupting agents. Although cardiac toxicity of such agents remains a possible issue, some of them have proceeded to Phase III clinical trials.
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Although hundreds of agents have been shown to influence microtubule dynamics in vitro, a large number of novel agents are currently being evaluated in clinical trials. These agents bind either to the vinca site, the taxane site or the colchicine site, although some novel agents seem to bind to other sites.
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Resistance mechanisms to microtubule-binding agents are complex and include ATP binding cassette efflux pumps, microtubular alterations and modifications in apoptotic signalling. Identification of these mechanisms has prompted the identification of novel agents indifferent to these resistance mechanisms.
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Although neurological toxicity remains a key issue associated with microtubule-binding agents, myeloid toxicity is usually manageable. The development of novel agents with reduced neurological toxicity or of assays that predict toxicity in individual patients are priorities for the optimization of this family of compounds.
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The long-term mutagenic effect of this family of agents has not yet been evaluated. Given the prolonged life expectancy of many patients treated with these compounds, this effect should be determined.
Abstract
Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. In the current search for novel microtubule-binding agents, enhanced tumour specificity, reduced neurotoxicity and insensitivity to chemoresistance mechanisms are the three main objectives.
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Acknowledgements
This work was supported in part by the Association pour la Recherche sur le Cancer and La Ligue contre le cancer. The video file was provided courtesy of Kathy Kamath, University of California Santa Barbara, USA.
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C.D. has received research funding from Pierre Fabre and Sanofi-Aventis and has worked as a consultant for Sanofi-Aventis and Bristol-Myers Squibb. M.A.J. has received research support from Bristol-Myers Squibb, Eisai Pharmaceuticals and Immunogen.
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Glossary
- Dynamic
-
The non-equilibrium behaviour of microtubules in cells. Microtubule dynamics are faster during mitosis than during interphase and are crucial to cell division, making mitotic cells highly susceptible to microtubule-targeted drugs. They are also important in cellular trafficking and for cell migration.
- Adjuvant therapy
-
A treatment that is administered to patients with minimal or no detectable sign of disease in order to prevent disease recurrence.
- Tubulin dimer
-
The heterodimeric protein subunit that polymerizes into microtubules. Each subunit is composed of one α-tubulin and one β-tubulin molecule.
- Tubulin isotype
-
Tubulin peptides with slightly different amino acid sequences. The isotype varies between cell types in the same tissue and between tissues and also differs between tumour and non-tumour cells. The distribution of tubulin isotypes can be induced to change in response to drug treatment.
- Rescue
-
The switch of a shortening microtubule end to growth or to a state of stable microtubule length.
- Catastrophe
-
The switch of a growing or stable microtubule end to rapid shortening.
- BCL-XL
-
B cell lymphoma extra large protein, an anti-apoptotic member of the BCL-2 family.
- Superacid transformation
-
Chemical modifications induced by exposure to an extremely acidic environment.
- Neutropaenia
-
Reduced granulocyte counts in blood, predisposing patients to infection.
- Corrected QT interval
-
The correlated QT interval is a heart rate corrected value that measures the time between the onset and the end of the heart's electrical cycle. A prolonged QT interval is a risk factor for ventricular tachyarrhythmias and sudden death.
- Myelosuppression
-
Inhibition of bone marrow function, leading to reduced numbers of red blood cells (anaemia), white blood cells (leukopaenia) and platelets (thrombocytopaenia).
- Kinetochore
-
The complex assemblage of proteins at the chromosome centromere to which dynamic mitotic spindle microtubules attach, ultimately producing equal segregation of chromosomes to the daughter cells.
- Grade 4 neuropathy
-
Neurological toxicity induced by exposure to microtubule-binding agents, most often manifested as pain and numbness.
- Iatrogenic leukaemia
-
Acute leukaemia caused by exposure to cancer chemotherapy; the prognosis is unfavourable.
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Dumontet, C., Jordan, M. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 9, 790–803 (2010). https://doi.org/10.1038/nrd3253
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DOI: https://doi.org/10.1038/nrd3253
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