Question

Certain cancer treatment drugs act by halting spindle fiber depolymerization. Why is this an effective mechanism? What limitations or risks does this come with?

Answer 1

Microtubules are long polymers made of smaller units of the protein tubulin. They are created by assembling (polymerizing) tubulin components, and are depolymerized when they are no longer needed. They are the major constituents of mitotic spindles, which is a structure used to move and separate chromosomes and other components of the cell during cell division. So cells use this tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process ever goes wrong it can lead to cancer.

MItotic inhibitors are ones which prevent cells from undergoing mitosis by disrupting microtubule polymerization, in order to prevent cancerous growth.

Anti-cancer drugs are developed which can target mitotic spindle and destroy dividing cells in tumours.

The microtubule-targeting agents (MTAs) are a very successful class of cancer drugs with therapeutic benefits in both hematopoietic and solid tumors . There are plenty of natural agents and their analogues foun to bind to soluble tubulin or directly to tubulin protein in the microtubules. Most of these include antimitotic agents which inhibit cell proliferation by acting on polymerization dynamics of mitotic spindles, which are very imortant for the proper spindle function of microtubules.

Microtubule-targeted antimitotic drugs are classified into two groups mainly. First group is microtubule-destabilizing agents, they inhibit microtubule polymerization at high concentrations and examples include compounds like the Vinca alkaloids (vinblastine, vincristine, vinorelbine, vindesine and vinflunine), cryptophycins, halichondrins, estramustine, colchicine and combretastatins. They are used clinically or are still under clinical investigation for treatment of cancer . second group is the microtubule-stabilizing agents. They stimulate microtubule polymerization, and include paclitaxel , docetaxel (Taxotere), the epothilones, and discodermolide.

However, the disadvantage is that microtubules are needed for many functions in non-cancerous cells. So sometimes treatments may not discriminate cancerous from normal cells. So the use of these agents can cause side effects such as nerve damage.

Some of the important side effects of vinca alkaloids are found to be peripheral neuropathy and reversible myelosuppression that commonly occur with these drugs. Neuropathy might result from disruption of axonal flow by bundling of microtubules by paclitaxel. It can be also because of microtubule destabilization or from suppression of microtubule dynamics due to neuronal retraction. Myelosuppression or bone marrow suppression can be a result of blockage of mitosis and proliferation of the rapidly cycling bone-marrow cells.