PACLITAXEL – MULTIPLE ROLES AS MICROTUBULE STABILIZER

Introduction: Mitosis and Cytokinesis

An essential part of the cell cycle is the M phase where the cell physically divides into two unique cells. This process is consists of two different phases mitosis and cytokinesis. Cytokinesis is the phase where the contents of the cell are divided into two equal portions along with the duplicate chromosomes and nuclei. The cell membrane then pinches together and eventually splits into two segments. Mitosis, on the other hand is the division of the duplicate chromosomes and nuclei into opposite ends of the cell. To do this; microtubule form from one end of the elongated cell to the newly formed chromosomes, these tubules then decrease in length pulling the chromosomes pairs apart. The same happens for the nuclei. This process is complex and involved but it is sufficient to indicate that action of inhibitors against the dismantling of the microtubules would halt the cell separation causing apoptosis to initiate [1-5]. A small molecule that can induce such a reaction is Paclitaxel microtubule stabilization has been used as the standard treatment for a variety of cancer types for many years.

Paclitaxel: Properties and Availability

Paclitaxel is often confused by researchers into believing this is a new molecule developed by Bristol-Myers as an analogue to taxol. However, Paclitaxel is the same molecule as Taxol and the name was altered for legal reasons. Paclitaxel was discovered in the 1960’s by the national cancer institute and initially developed by them. This molecule was named Taxol by the research staff and registered as per normal. When costs for developing Taxol increased beyond the institute’s ability to cover an agreement was reached with Bristol-Myers to continue the development. Bristol-Myers developed taxol into a successful chemotherapy agent, to preserve their rights the name Taxol was changed to Paclitaxel.

Paclitaxel structure is such that the Paclitaxel solubility is extremely poor in aqueous solution making formulation difficult. To combat this Paclitaxel manufactures used cremphor as a solvent to keep it in solution until systemic proteins could bind and carry the molecule to its site of action. However, cremphor has recently been linked with a series of extreme toxic side effects hence the usual formulation is under question. Abraxane is Abraxis bioscience solution to this problem where Paclitaxel has been bound to a nanoparticle albumin [6]. The result is a soluble injectable formulation that has less toxicity than the traditional formulation. Paclitaxel stability is delicate and solutions must be kept at -20°C in the absence of strong alkali’s and acids. Paclitaxel cost is variable reflecting the degree of purity, formulation and which Paclitaxel supplier the stock is purchased from. Paclitaxel prices range from $43 - $2000 per 100mg which is lsightly worrying is you are a researcher looking to buy Paclitaxel.

Paclitaxel: Preclinical research and clinical status

With the recent knowledge that cremphor is causing many of the toxic side effects seen with this drug different Paclitaxel mechanisms for targeted delivery are being developed [7-10]. One of the more successful techniques is that of the Paclitaxel poliglumex, this formulation is similar to the protein bound Abraxane but instead of a protein Paclitaxel has a polyglutamate series bound to it. Since polyglutamation is a natural clearance process this has the effect of increase Paclitaxel’s solubility and enhances it permeability towards cellular accumulation. This formulation however, did not meet it primary end points at phase III in NSCLC, indicating similar performance to traditional formulations [11;12]. What it did show, though, was a significant change in the degree of toxicity seen improving patient’s quality of life. Paclitaxel assays have been published extensively in literature covering all aspects of biological material. Pharmacokinetic data is available for various patient groups enabling statistical assessment of patient groups refining treatment profiles [7;13].

Paclitaxel clinical trials have been conducted in all areas of tumor growth types and Paclitaxel breast cancer approval was reached in 1994 [14-30]. For Paclitaxel ovarian cancer therapy it is recommended for second line use following failure of platinum treatment a similar finding was reported for Paclitaxel lung cancer therapy. Paclitaxel continues to outperform most other chemotherapy agents in terms of broad spectrum response and looks to continue to do so for the foreseeable future.

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