Microtubule Inhibitors

Summary

Mechanisms

The vinca alkaloids, which include vincristine and vinblastine inhibit microtubule assembly (polymerization).
The taxanes, which include paclitaxel inhibit microtubule disassembly (depolymerization, producing overpolymerization).

Peripheral Neuropathy

Both the vinca alkaloids and the taxanes can produce neuropathy, which we represent as a stocking-glove distribution of sensory disturbance (pain, tingling, and loss of sensation).

Mechanisms: Mitosis

Mitosis

Metaphase: Chromosomes line up along the metaphase plate; microtubules stretch out and attach at their kinetochores.
Anaphase: Microtubules (specifically, kinetochore microtubules) shorten and pull the chromosomes toward the spindle poles: the sister chromatids are drawn to opposite spindle poles.

Inhibition

Microtubule inhibitors arrest cell division in metaphase; they prevent the cell from passing the metaphase/anaphase checkpoint (arrest in the G2/M phase).

Microtubule Structure

Alpha tubulin and beta tubulin join to form alpha-beta tubulin heterodimers. They then aggregate into protofilaments and lattices, and ultimately into microtubules, which are hollow cylinders (tubes).

Vinca Alkaloids

Vinca alkaloids (vincristine and vinblastine) block tubulin polymerization: microtubule assembly/aggregation.

Note that colchicine, which is used in gouty arthritis, is also another well-known microtubule assembly inhibitor.

Taxanes

Summary

Thus, vinca alkaloids and taxanes prevent the progression of DNA replication through the metaphase/anaphase checkpoint in mitosis through interference of microtubule assembly (in the case of vinca alkaloids) and disassembly (in the case of the taxanes).

Chemotherapy Induced Peripheral Neuropathy (CIPN)

Key Causes

Vincristine, of the vinca alkaloids – they prevent microtubule polymerization.
Paclitaxel, of the taxanes – they prevent microtubule depolymerization (produce overpolymerization).
Oxaliplatin, as well as cisplatin of the platinum agents (remember cisplatin it is an OCT2 substrate and OCT2 has an affinity for uptake in the dorsal root ganglion).
Bortezomib, a proteasome inhibitor.
Thalidomide, which is, amongst other things an antiangiogenic, IL-6 inhibitor.

Stocking-Glove Distribution

CIPN produces a classic “stocking-glove” distribution of sensory loss/pain/paresthesias that manifests in a “dying-back” progression.

Toxicity to Dorsal Root Ganglion, Nerve Endings, & Subcellular Components

There is injury at the dorsal root ganglion, which houses the sensory neurons. Sensory symptoms predominate, at least in part, because the dorsal root ganglion lacks a nervous system barrier (like the brain does (ie, the blood-brain barrier), which makes it particularly vulnerable to toxins because it: it isn’t protected from the systemic vasculature in the way other major nervous system structures are.
Also, direct neurotoxicity at the nerve endings, the distal nerve terminals.
Also, toxicity to some notable cellular components along the nerve axon are proposed to produce the neuropathy. They include microtubules (remember that vinca alkaloids and taxanes are microtubule inhibitors); mitochondria, which have their own DNA; and ion channels.
Unfortunately, no clear-cut CIPN preventative or treatment has been discovered, as of 2022.