24.03.4 Microtubule Inhibitors

The mitotic spindle is part of a larger intracellular network of microtubules that is formed during prophase in the cell cycle. This role of this larger network, termed the cytoskeleton, is to move cytoplasmic structures around the cell. The mitotic spindles, which comprise chromatin plus a system of tubulin microtubules, attach to the centromeres of the chromosomes and facilitate the equal partitioning of newly replicated DNA from the parent cell into the two daughter cells during anaphase in eukaryotic cell division. A number of plant-derived compounds, the microtubule inhibitors, are able to disrupt the assembly and disassembly mechanism of tubulin polymerisation thereby causing cytotoxicity.

The microtubule inhibitors comprise two groups, the vinca alkaloids and the taxanes (taxols), which can be distinguished by their different modes of action on the microtubule.

The vinca alkaloids comprise vincristine and vinblastine, which are structurally related compounds derived from the periwinkle plant, Vinca rosa, and vinorelbine which is a newer, less toxic semi-synthetic analogue. All three vinca alkaloids have the same mode of action and are deemed to work in a cell-cycle specific manner. They bind to the microtubule protein tubulin and block its ability to polymerise and form microtubules. Instead aggregates of tubulin dimmers and alkaloid drugs are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation.

Although the vinca alkaloids share a related structure, their therapeutic indications are different. Vincristine is used in acute lymphoblastic leukaemia, Hodgkin’s and non-Hodgkin’s lymphoma and some solid tumours whereas vinblastine, though also used to treat lymphoma, is used to treat metastatic testicular carcinoma. Vinorelbine is beneficial in the treatment of advanced non-small cell lung cancer. Generalised adverse effects such as nausea, vomiting, diarrhoea and alopecia are observed with these drugs whilst more serious adverse reactions such as peripheral neuropathy (including parasthesias and ataxia), phlebitis (inflammation of veins of the legs and arms) and severe myelosuppression have been noted. All of the vinca alkaloids are generally administered with other anticancer drugs.

The second group of microtubule inhibitors are the taxanes (also known as the taxols). These comprise paclitaxol (better known as taxol) which is isolated from the Pacific yew tree and docetaxol, a semisynthetic structural analogue of paclitaxol.

Although, the taxanes are classified as microtubule inhibitors and are cell-cycle specific, they have a mechanism of action which is distinct from the vinca alkaloids. The taxanes bind to a different site on tubulin from the vinca alkaloids, promoting rather than inhibiting microtubule formation. This results in unusually stable non-functional microtubules that fail to depolymerise, subsequently stopping chromosome desegregation and causing cell death.

The taxanes have been shown to be effective in the treatment of advanced ovarian cancer, metastatic breast cancer and non-small cell lung cancer particularly when used in conjunction with other anticancer drugs. A decrease in the neutrophil blood count (neutropaenia) as a result of taxane administration is the most serious adverse reaction to these drugs and treatment should be discontinued if it occurs. Other adverse effects associated with these drugs include bradycardia (slowing of heart rate), fluid retention, alopecia and, in rare cases, vomiting and diarrhoea. Because of serious hypersensitivity including hypotension, a patient who is to be treated with paclitaxel should be pre-treated with dexamethasone and antihistamines.