ABSTRACT
This chapter introduces the tubulin inhibitors which, along with the antimetabolites and DNA-interactive agents, are one of the oldest families of cytotoxic agents still used in the clinic. It first provides an introduction to the microtubules which are highly dynamic cytoskeletal polymers existing in a continuous dynamic state of lengthening and shortening at both ends by reversible association and dissociation of α/β-tubulin heterodimers. They are present in all eukaryotic cells and serve as an essential structural component within the cell, important for a number of functions including maintenance of cell shape and polarization, cytokinesis, mitosis, cell motility, intracellular transport, secretion, and vesicular transport. Not surprisingly, the presence of an agent that suppresses microtubule dynamics can block the cell cycle and result in cell death through apoptosis. Next, the various subfamilies of tubulin inhibitors are discussed including the Vinca alkaloids and the taxanes, the first to be introduced into clinical practice in the 1960s and 1990s, respectively, and the more recently introduced epothilone and halichondrin B subfamilies. Approved agents within each subfamily are described in detail along with information relating to their discovery, chemical structure, mechanism of action, pharmacology, clinical activity, and mechanism-based toxicity. A discussion of structure-activity relationships (SARs) is included within subfamilies where relevant. Prominent clinical-stage experimental agents within each subfamily are also described, and a section on new approaches to targeting tubulin is provided.
