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PACLITAXEL – A MICROTUBULE INHIBITOR WITH MULTIPLE ROLES

by Selleckchem | Apr 04 2012

PACLITAXEL:
Paclitaxel is an inhibitor of mitosis and it was discovered in the bark of a tree called Taxus brevifolia and later on its presence was also reported in hazel cells. Many of the cancer drugs target microtubules in the cancer cells [1], Paclitaxel microtubules inhibitor is a new hope for cancer treatment. The structure of this compound is complex as it contains diterpene along with an oxatane ring and taxane. The generic name has been changed by the manufacturers of Paclitaxel that was Taxol the brand name of this inhibitor is Abraxane and any one can buy Paclitaxel for medicinal usage. Paclitaxel is soluble in methanol and DMSO and in order to gain long term stability for this compound one should keep it away from any strong acidic or alkaline solution. The Paclitxel price is variable as it depends on its purity and Paclitaxel supplier. Its cost is reasonable and one can purchase Paclitaxel for research purposes as well.
Derivatives of Paclitaxel are also present and one of these is Paclitaxel poliglumex which has a polyglutamate polymer that increases its hydrophilicity hence making its delivery to tumor site or cells more easy [2], this derivative is also used against many cancers successfully including non small cell lung cancer or NSCLC [3]. Beyond this various other inventions are also increasing its efficacy for example Herceptin was noted to be more effective in its anti-cancer ability when applied to xenografts of breast cancer [4]. Paclitaxel also inhibits the formation of vessels [5]. In coronary surgeries Paclitaxel stents are also used [6], and reducing hyperplasia [7].

PACLITAXEL EFFICIENCY ASSESMENT:
Paclitaxel efficiency has been analyzed by various methods like including ATP-cell viability assay [8], HPLC (high performance liquid chromatography) [9], FISH (florescent in-situ hybridization) along with comet assay [10], Liquid Chromatography Mass Spectroscopy [11], solid phase extraction coupled with HPLC and Ultraviolet detection [12]etc. are mostly used for efficient results.
The action mechanism of Paclitaxel is by stabilizing polymer of microtubules and to hinder its disassembly to check mitosis which stimulates programmed cell death or apoptosis over a long time period. In case of Kaposi sarcoma the mechanism of Paclitaxel involves down regulation of apoptosis inhibitor BCl-2 gene which leads to apoptosis [13]. TNF-ß(Tumor Necrosis Factor) is released during the Paclitaxel actions in mouse model tumor cells which ultimately resulted into apoptosis that is independent to p-53 gene [14]. The cell cycle is arrested during G2/M phase where mitotic assembly is stopped in cell [15] another feature of Paclitaxel is reported as it also induces apoptosis by caspase-8 [16].

PACLITAXEL CLINICAL TRIALS:
Various cancers are reported to be treated by Paclitaxel during its clinical trials, hence proving a remarkable success in all the phases of clinical trials. In case of ovarian cancer this inhibitor has more preference over use of Topotecan [17] and in clinical trials phase-II, Paclitaxel has also been preferred over conventional therapy based on platinum [18]. During phase II of clinical trials Paclitaxel was used for ovarian cancer alone or in combination with other agents like Cisplatin [19] [20] another combination was also favored with Carboplatin [21] and also with Cyclophosphamide [22] for better results.
In lung cancer studies Paclitaxel was proved successful against NSCLC in phase II trials [23] and during phase III the performance of Paclitaxel and poliglumex was much effective than Docetaxel [24]. Many other drugs are also used with this drug [25] and for the best combination to treat lung cancer these combinations are studied thoroughly [26]. In breast cancer trials both Paclitaxel and Doxorubicin showed efficient results [27]. Not only these combinations but also many other chemical agents including Epirubicin and Trastuzumab etc. had good results [28] for the validation of these results phase III studies on breast cancer are done [29].

REFERENCES:
1. Jordan, M.A.a.W., L., Microtubules as a target for anticancer drugs. Nat Rev Cancer, 2004.
2. Singer, J.W.e.a., Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. Anticancer Drugs, 2005.
3. Bonomi, P.e.a., Paclitaxel poliglumex (PPX, CT-2103): macromolecular medicine for advanced non-small-cell lung cancer. Expert Rev Anticancer Ther., 2007. 7(4): p. 415-22.
4. Baselga, J.e.a., Recombinant Humanized Anti-HER2 Antibody (Herceptin™) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER2/neu Overexpressing Human Breast Cancer Xenografts. Cancer Res, 1998.
5. Belotti, D.e.a., The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Can Res, 1996.
6. Stone, G.W.e.a., One-Year Clinical Results With the Slow-Release, Polymer-Based, Paclitaxel-Eluting TAXUS Stent. Circulation, 2004.
7. Hong, M.e.a., Paclitaxel Coating Reduces In-Stent Intimal Hyperplasia in Human Coronary Arteries. Circulation, 2003.
8. Untch, M.e.a., Comparison of paclitaxel and docetaxel (Taxotere) in gynecologic and breast cancer cell lines with the ATP-cell viability assay. Anti Cancer Drugs, 1994.
9. Lee, S.e.a., Rapid and sensitive determination of paclitaxel in mouse plasma by high-performance liquid chromatography. Journal of Chromatography, 1999.
10. Digue, L.e.a., Evaluation of the genotoxic activity of paclitaxel by the in vitro micronucleus test in combination with fluorescent in situ hybridization of a DNA centromeric probe and the alkaline single cell gel electrophoresis technique (comet assay) in human T-lymphocytes. Environmental and Molecular Mutagenesis, 1999.
11. Parise, R.A.e.a., Sensitive liquid chromatography-mass spectrometry assay for quantitation of docetaxel and paclitaxel in human plasma. Journal of Chromatography B, 2003.
12. Andersen, A.e.a., High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection. BMC Clinical Pharmacology, 2006.
13. Sgadari, C.e.a., Mechanism of Paclitaxel Activity in Kaposi’s Sarcoma. The Journal of Immunology, 2000.
14. Lanni, J.S.e.a., p53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proceedings of National Academy of Sciences of the USA, 1997.
15. Horwitz, S.B., Taxol (paclitaxel): mechanisms of action. Ann Oncol., 1994.
16. Mielgo, A.e.a., Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules. Oncogene, 2009.
17. Huinink, W.B.e.a., Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. Journal of Clinical Oncology, 1997. 15(2183-2193).
18. Parmar, M.K.e.a., Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet, 2003. 361(9375): p. 2099-106.
19. Muggia, F.M.e.a., Phase III Randomized Study of Cisplatin Versus Paclitaxel Versus Cisplatin and Paclitaxel in Patients With Suboptimal Stage III or IV Ovarian Cancer: A Gynecologic Oncology Group Study. Journal of Clinical Oncology, 2000. 18 (1): p. 106.
20. Armstrong, D.K.e.a., Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer. N Engl J Med, 2006. 354: p. 34-43.
21. Ozols, R.F.e.a., Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study. Journal of Clinical Oncology, 2003. 21(17): p. 3194-3200.
22. McGuire, W.P.e.a., Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian Cancer. N Engl J Med, 1996. 334: p. 1-6.
23. Johnson, D.H.e.a., Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 2004.
24. Ares, L.e.a., Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. British Journal of Cancer, 2008. 98: p. 1608-1613.
25. Sandler, A.e.a., Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer. N Engl J Med, 2006.
26. Mavroudis, D.e.a., A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol, 2001.
27. Sledge, G.W.e.a., Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). Journal of Clinical Oncology, 2003.
28. Buzdar, A.U.e.a., Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer. Journal of Clinical Oncology, 2005.
29. Miller, K.e.a., Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N Engl J Med, 2007.