colchicine

colchicine, alkaloid extracted from plants of the genus Colchicum and especially from the corms of the autumn crocus, Colchicum autumnale (see meadow saffron). The metabolic effect of colchicine is not known, but it is thought that it may decrease production of lactic acid and prevent accumulation of uric acid crystals in the body, making it useful in the treatment of gout. Colchicine and derivatives such as demecolcine inhibit mitosis, or cell division. As a mitotic poison, it inhibits rapidly proliferating cells and has been used in cancer therapy and as an immunosuppressive drug. Colchicine has also been used to visualize chromosomes photomicrographically and to induce mutations experimentally.

Colchicine is a highly poisonous natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (Autumn crocus, Colchicum autumnale, also known as the "Meadow saffron"). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. Its present medicinal use is mainly in the treatment of gout; as well, it is being investigated for its potential use as an anti-cancer drug. It can also be used as initial treatment for pericarditis and preventing recurrences of the condition. In neurons, axoplasmic transport is disrupted by colchicine.

History

Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides in the first century CE.

The colchicine alkaloid was first isolated in 1820 by the two French chemists P.S. Pelletier and J. Caventon.

It was later identified as a tricyclic alkaloid, and its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

Pharmacology

Biological function

Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison. Since one of the defining characteristics of cancer cells is a significantly increased rate of mitosis, this means that cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. However, the therapeutic value of colchicine against cancer is (as is typical with chemotherapy agents) limited by its toxicity against normal cells.

Apart from inhibiting mitosis, a process heavily dependent on cytoskeletal changes, colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect. Colchicine also inhibits urate crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. The inhibition of uric acid crystals is a vital aspect on the mechanism of gout treatment.

Colchicine as medicine

Colchicine is Food and Drug Administration (FDA)-approved for the treatment of gout and also for familial Mediterranean fever, secondary amyloidosis(AA), and scleroderma. It is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.

The Australian biotechnology company Giaconda has developed a combination therapy to treat constipation-predominant irritable bowel syndrome which combines colchicine with the anti-inflammatory drug olsalazine.

The British drug development company Angiogene is developing a prodrug of colchicine, ZD6126 (also known as ANG453) as a treatment for cancer.

Colchicine has a relatively low therapeutic index.

Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.

Side effects

Side effects include gastro-intestinal upset and neutropenia. High doses can also damage bone marrow and lead to anaemia. Note that all of these side effects can result from hyper-inhibition of mitosis.

Toxicity

Colchicine poisoning has been compared to arsenic poisoning: symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure. Death from respiratory failure can follow. There is no specific antidote for colchicine, although various treatments do exist.

Botanical use

Since chromosome segregation is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes therefore contain no chromosomes, while the other half contain double the usual number of chromosomes (i.e., diploid instead of haploid as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e. tetraploid instead of diploid). While this would be fatal in animal cells, in plant cells it is not only usually well tolerated, but in fact frequently results in plants which are larger, hardier, faster growing, and in general more desirable than the normally diploid parents; for this reason, this type of genetic manipulation is frequently used in breeding plants commercially. In addition, when such a tetraploid plant is crossed with a diploid plant, the triploid offspring will be sterile, which may be commercially useful in itself by requiring growers to buy seed from the supplier, but also can often be induced to create a "seedless" fruit if pollinated (usually the triploid will also not produce pollen, therefore a diploid parent is needed to provide the pollen). This is the method used to create seedless watermelons, for instance. On the other hand, colchicine's ability to induce polyploidy can be exploited to render infertile hybrids fertile, as is done when breeding triticale from wheat and rye. Wheat is typically tetraploid and rye diploid, with the triploid hybrid infertile. Treatment with colchicine of triploid triticale gives fertile hexaploid triticale.

When used to induce polyploidy in plants, colchicine is usually applied to the plant as a cream. It has to be applied to a growth point of the plant, such as an apical tip, shoot or sucker. Seeds can be presoaked in a colchicine solution before planting. As colchicine is so dangerous, it is worth noting that doubling of chromosome numbers can occur spontaneously in nature, and not infrequently. The best place to look is in regenerating tissue. One way to induce it is to chop off the tops of plants and carefully examine the lateral shoots and suckers to see if any look different.

References

External links

• Feature on colchicine, by Matthew J. Dowd at vcu.edu