In 1980 a group of scientists at the Albert Einstein Medical College reported it's findings on Taxol. These ground breaking findings reported that the mode of action of Taxol was totally unique. Unlike other traditional anticancer agents, such as colchicine, vincristine, podophylotoxin and maytansine, Taxol promotes microtuble polymerisation and hence stabilises them to the extent that mitosis is disrupted.
These findings generated renewed interest in taxol and this led to major problems when research groups wanted to carry out clinical trials, which required large quantities of the material (see Section on 'Methods of Obtaining Taxol').
At the time Taxol was the only known compound to exhibit this type of activity. It has since been shown that the epothilone family of molecules also have the same mode of activity.
Taxol is a potent anticancer agent which targets rapidly dividing cancer cells and prevents them from replicating. Microtubules, made of polymerised tubulin, are essential in the normal functioning of a cell and also play important roles as the basis of the cellular skeleton and the movement of organs. One of the more important functions of microtubules is observed during cell replication (mitosis).
A brief explanation of mitosis is required to understand how Taxol and it's anticancer acting derivatives effect this process and stops the replication of cancer cells.The process of cell replication (1), mitosis, is as follows:-
ELECTRON MICROGRAPHS SHOWING THE PROCESS OF
MITOSIS
PICTURES OF TUBULIN AND
MICROTUBULES
Taxol prevents the mother cell from assembling spindle fibres by making it's components more rigid and hence more difficult to work with. The extreme flexibility of the tubulin protein (important constituent of microtubules) enables microtubules to shift to different forms (microtubule -> spindle fibres -> microtubule). Taxol has been described as a 'mitotic stabiliser' and when it binds to tubulin, the protein loses it's flexibility and the micotubules can no longer disassemble. This disrupts mitosis and cell replication no longer occurs.
The selectivity displayed by Taxol and many other anticancer drugs, is due to the fact that that cancer cells replicate more frequently than 'normal' body cells and thus are more strongly affected by the presence of the drug.
A more detailed explanation of the mechanism of the anti mitotic agent can be viewed by clicking the following link:-
DETAILED METHOD OF TAXOL DELIVERY
Taxol enhances both the rate and yield of microtubule assembly. The critical concentration of microtubule protein required for assembly is reduced, and the microtubules formed are stable to deploymerization by calcium or low temperatures (Schiff et al. ). This unusual stability inhibits the normal dynamic reorganisation of the microtubule network.
When Taxol binds to the tubulin it not only interferes with mitosis, but also with many other biological functions involving microtubules:-
Taxol also decreases the secretion of various proteins, such as: plasma proteins, insulin, prothrombinase and catecholamine. There is also an increase in the secretion of Tumour Necrosis Factor (TNF) which sometimes plays an important role in the fight against the tumour.
Studies have shown that Taxol will bind only to tubulin that has been polymerised into chains of protofilaments (linear tubulin chains), and not to tubulin dimers (2).
All the effects of Taxol appear to be related to the Tubulin-Microtubule system.
The evidence supporting this theory are as follows:-
(1) The Molecular Biology of The Cell : 3rd edition, Albert.B ,Bray.D ,Lewis.J ,Raff.M , Roberts. K ,Watson. J.D .
(2) Einzig, A.I.; Hochster, H.; Wiernik,
P.H. Investigational New Drugs. 1991, 9, 59-64
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