Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Open Medicine

formerly Central European Journal of Medicine

Editor-in-Chief: Darzynkiewicz, Zbigniew


IMPACT FACTOR 2018: 1.221

CiteScore 2018: 1.01

SCImago Journal Rank (SJR) 2018: 0.329
Source Normalized Impact per Paper (SNIP) 2018: 0.479

ICV 2017: 152.94

Open Access
Online
ISSN
2391-5463
See all formats and pricing
More options …
Volume 6, Issue 5

Issues

Volume 10 (2015)

Paclitaxel as an anticancer agent: isolation, activity, synthesis and stability

Vesna Nikolic / Ivan Savic / Ivana Savic / Ljubisa Nikolic / Mihajlo Stankovic / Valentina Marinkovic
Published Online: 2011-08-09 | DOI: https://doi.org/10.2478/s11536-011-0074-5

Abstract

Paclitaxel is isolated from the Pacific yew. It can be obtained from the European yew, but only after chemical modification of the isolated compound by a semi-synthesis procedure. The procedure for total synthesis of paclitaxel is very complicated, involving multiple steps, and the yields of paclitaxel are meagre. This substance is also a metabolite of certain kinds of fungus. The microbiological pathway for producing paclitaxel compared with isolation from plant material involves shorter procuction times but a small yield. Cyclodextrins are usually used for improving the solubility of paclitaxel in aqueous media, with polymeric and other substances added. Paclitaxel has anticancer activity and use for preparing the formulations intravenously administrated to patients with tumors. The paclitaxel concentration in these formulations is determined using validated HPLC methods.

Keywords: Paclitaxel; Isolation; Activity; Synthesis; Complexation

  • [1] Rowinsky E.K., Donehower R.C., Paclitaxel (taxol). N. Engl. J. Med., 1995, 332, 1004–1014 http://dx.doi.org/10.1056/NEJM199504133321507CrossrefGoogle Scholar

  • [2] Wani M.C., Taylor H.L., Wall M.E., Coggan P., McPhail A.T., Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia, J. Am. Chem. Soc., 1971, 93, 2325–2327 http://dx.doi.org/10.1021/ja00738a045CrossrefGoogle Scholar

  • [3] Schiff PB, Fant J, Horwitz SB; Promotion of microtubule assembly in vitro by taxol. Nature 1979;(227):665–667 Google Scholar

  • [4] Schiff P.B., Horwitz S.B., Taxol stabilizes microtubules in mouse fibroblast cells, PNAS 1980, 77, 1561–1565 http://dx.doi.org/10.1073/pnas.77.3.1561CrossrefGoogle Scholar

  • [5] Rowinsky E.K., Cazenave L.A., Donehower R.C., Taxol: a novel investigational antimicrotubule agent, J. Natl. Cancer I 1990, 82, 1247–1259 http://dx.doi.org/10.1093/jnci/82.15.1247CrossrefGoogle Scholar

  • [6] Stierle A., Strobel G., Stierle D., Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of pacific yew, Science 1993, 260, 214–216 http://dx.doi.org/10.1126/science.8097061CrossrefGoogle Scholar

  • [7] Guo B.H., Kai G.Y., Jin H.B., Tang K.X., Taxol synthesis. Afr. J. Biotechnol. 2006, 5(1), 15-20 Google Scholar

  • [8] Strobel G., Yang X.S., Sears J., Kramer R., Sidhu R.S., Hess W.M., Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana, Microbiology 1996, 142, 435–440 http://dx.doi.org/10.1099/13500872-142-2-435CrossrefGoogle Scholar

  • [9] Li J.Y., Stroble G., Sidhu R., Hess W.M., Ford E.J., Endophytic Taxolproducing fungi from bald cypress. Taxodium distichum, Microbiology 1996, 142, 2223–2226 Google Scholar

  • [10] Wang J.F., Li G.L., Lu H.Y., Zheng Z.H., Huang Y.J., Su W.J., Taxol from Tubercularia sp. strain TF5, an endophytic fungus of Taxus mairei, FEMS Microbiol. Lett. 2000, 193, 249–253 http://dx.doi.org/10.1111/j.1574-6968.2000.tb09432.xCrossrefGoogle Scholar

  • [11] U. Breme, M. Caruso, N.C. Perellino, L. Fedeli, A. Pavesi, L. Piacenza, G. Ventrella, 2003. Paclitaxel production by Actinomycetes. U.S. patent 6,528,301 Google Scholar

  • [12] Adler L.M., Herzog T.J., Williams S., Rader J.S., Mutch D.G., Analysis of exposure times and dose escalation of paclitaxel in ovarian cancer cell lines, Cancer 1994, 74, 1891–1898 http://dx.doi.org/10.1002/1097-0142(19941001)74:7<1891::AID-CNCR2820740711>3.0.CO;2-KCrossrefGoogle Scholar

  • [13] Richheimer S.L., Tinnermeier D.M., Timmons D.W., High-performance liquid chromatographic assay of taxol, Anal. Chem. 1992, 64(20), 2323–2326. http://dx.doi.org/10.1021/ac00044a004CrossrefGoogle Scholar

  • [14] Vyas D.M., Kadow J.F., Paclitaxel: A Unique Tubulin Interacting Anticancer Agent, Progr. Med. Chem. 1995, 32, 289–337 http://dx.doi.org/10.1016/S0079-6468(08)70456-9CrossrefGoogle Scholar

  • [15] Xu Q., Trissel L.A., Martinez J.F., Stability of paclitaxel in 5% dextrose injection or 0.9% sodium chloride injection at 4, 22, or 32 °C, Am. J. Hosp. Pharm. 1994, 51, 3058–3060 Google Scholar

  • [16] T.B. Khac, M. Potier, 2004. Process for isolation and purification of paclitaxel from natural sources. U.S. patent 6,759,539 Google Scholar

  • [17] S.S.K. Foo, Y. Bai, M. Ehlert, 2000. Method for high yield and large scale extraction of paclitaxel from paclitaxel-containing material. U.S. patent 6,136,989 Google Scholar

  • [18] Kawamura F, Kikuchi Y, Ohira T, Yatagai M. Accelerated Solvent Extraction of Paclitaxel and Related Compounds from the Bark of Taxus cuspidate. J. Nat. Prod. 1999, 62(2), 244-247 CrossrefGoogle Scholar

  • [19] Zu Y., Wang Y., Fu Y., Li S., Sun R., Liu W., Luo H., Enzyme-assisted extraction of paclitaxel and related taxanes from needles of Taxus chinensis, Sep. Purif. Technol. 2009, 68(2), 238–243 http://dx.doi.org/10.1016/j.seppur.2009.05.009CrossrefGoogle Scholar

  • [20] P. Vemishetti, F.S. Gibson, J.L. Dillon, 2001. Semisynthesis of paclitaxel using dialkyildichlorosilanes. U.S. patent 6,242,614 B1 Google Scholar

  • [21] Denis J.N., Greene A.E., Guenard D., Voegelein F.G., Potier L.M.P., Highly efficient, practical approach to natural taxol, J. Am. Chem. Soc. 1988, 110(17), 5917–5919 http://dx.doi.org/10.1021/ja00225a063CrossrefGoogle Scholar

  • [22] R.A. Holton, 1993. Metal alkoxides. U.S. patent 5,274,124 Google Scholar

  • [23] M.A. Poss, J.L. Moniot, I.D. Trifunovich, D.J. Kucera, J.K. Thottathil, S.H. Chen, J. Wei, 1994. Novel sidechain-bearing taxanes and intermediates thereof. W.O. patent 9414787 Google Scholar

  • [24] Kingston D.G.I., Chaudhary A.G., Gunatilaka A.A.L., Middleton M.L., Tetrahedron. Lett. 1994, 35, 4483–4484 http://dx.doi.org/10.1016/S0040-4039(00)60706-2CrossrefGoogle Scholar

  • [25] Commerçon A., Bézard D., Bernard F., Bourzat J.D., Improved protection and esterification of a precursor of the taxotere® and taxol side chains, Tetrahedron. Lett. 1992, 33(36), 5185–5188 http://dx.doi.org/10.1016/S0040-4039(00)79128-3CrossrefGoogle Scholar

  • [26] Holton R.A., Somoza C., Kim H.B., Liang F., Biediger R.J., Boatman P.D., Shindo M., Smith C.C., Kim S., Nadizadeh H., Suzuki Y., Tao C., Yu P., Tang S., Zhang P., Murthi K.K., Gentile L.N., Liu J.H., First total synthesis of Taxol, J. Am. Chem. Soc. 1994, 116, 1597–1600 http://dx.doi.org/10.1021/ja00083a066CrossrefGoogle Scholar

  • [27] Nicolaou K.C., Yang Z., Liu J.J., Ueno H., Nantermet P.G., Guy R.K., Claiborne C.F., Renaud J., Couladouros E.A., Paulvannan K., Sorensen E.J., Total synthesis of Taxol, Nature 1994, 367, 630–634 http://dx.doi.org/10.1038/367630a0CrossrefGoogle Scholar

  • [28] Danishefsky S.J., Master J.J., Young W.B., Link J.T., Snyder L.B., Magee T.V., Jung D.K., Isaacs R.C.A., Bornmann W.G., Alaimo C.A., Coburn C.A., Di Grandi M.J., Total Synthesis of Baccatin III and Taxol, J. Am. Chem. Soc. 1996, 118, 2843–2859 http://dx.doi.org/10.1021/ja952692aCrossrefGoogle Scholar

  • [29] Morihira K., Hara R., Kawahara S., Nishimori T., Nakamura N., Kusama H., Kuwajima I., Enantio-selective total synthesis of Taxol, J. Am. Chem. Soc. 1998, 120, 12980–12981 http://dx.doi.org/10.1021/ja9824932CrossrefGoogle Scholar

  • [30] Nikolic V., Stankovic M., Kapor A., Nikolic Lj., Cvetkovic D., Stamenkovic J., Allylthiosulfinate: β-Cyclodextrin Inclusion Complex: Preparation, Characterization and Microbiological Activity, Die Pharmazie 2004, 59(11), 845–848 Google Scholar

  • [31] Nikolic V., Nikolic Lj., Stankovic M., Kapor A., Popsavin M., Cvetkovic D., A molecular inclusion complex of atenolol with 2-hydroxypropyl-β-cyclodextrin; production and characterization thereof, J. Serb. Chem.Soc. 2007, 72(8–9), 737–746 http://dx.doi.org/10.2298/JSC0709737NCrossrefGoogle Scholar

  • [32] Nikolic V., Ilic D., Nikolic Lj., Stankovic M., Cakic M, Stanojevic Lj., Kapor A., Popsavin M., The protection of Nifedipin from photodegradation due to complex formation with β-cyclodextrin, Cent. Eur. J. Chem. 2010, 8(4), 744–749 http://dx.doi.org/10.2478/s11532-010-0043-xCrossrefGoogle Scholar

  • [33] Savic I., Nikolic G., Savic I., Cakic M., Studies of the forced hydrolysis degradation of copper complexes with different oligosaccharides, Russ. J. Phys. Chem. A 2010, 84(13), 2306–2313 http://dx.doi.org/10.1134/S0036024410130170CrossrefGoogle Scholar

  • [34] Savic I., Nikolic G., Savic I., Cakic M., Conductometric studies on the stability of copper complexes with different oligosaccharides, Cent. Eur. J. Chem. 2010, 8(5), 1078–1085 http://dx.doi.org/10.2478/s11532-010-0082-3CrossrefGoogle Scholar

  • [35] Sharma U.S., Balasubramanian S.V., Straubinger R.M., Pharmaceutical and physical properties of paclitaxel (Taxol) complexes with cyclodextrins, J. Pharm. Sci. 1995,84(10), 1223–1230 http://dx.doi.org/10.1002/jps.2600841015CrossrefGoogle Scholar

  • [36] Hamada H., Ishihara K., Masuoka N., Mikuni K., Nakajima N., Enhancement of Water-Solubility and Bioactivity of Paclitaxel using Modified Cyclodextrins, J. Biosci. Bioeng. 2006, 102(4), 369–371 http://dx.doi.org/10.1263/jbb.102.369CrossrefGoogle Scholar

  • [37] Dordunoo S.K., Burt H.M., Solubility and stability of paclitaxel: effects of buffers and cyclodextrins, Int. J. Pharm. 1996, 133, 191–201 http://dx.doi.org/10.1016/0378-5173(96)04443-2CrossrefGoogle Scholar

  • [38] R. Yong, G. Jianfeng, Y. Shuqin, W. Ling, 2009. Pharmaceutical composition comprising cyclodextrin paclitaxel inclusion and preparation method thereof. Eu patent 075010 Google Scholar

  • [39] Lee S.C., Huh K.M., Lee J., Cho Y.W., Galinsky R.E., Park K., Hydrotropic Polymeric Micelles for Enhanced Paclitaxel Solubility: In Vitro and In Vivo Characterization, Biomacromolecules 2007, 8(1), 202–208 http://dx.doi.org/10.1021/bm060307bCrossrefGoogle Scholar

  • [40] Ma G., Yang J., Zhang L., Song C., Effective antitumor activity of paclitaxel-loaded poly (ɛ-caprolactone)/pluronic F68 nanoparticles after intratumoral delivery into the murine breast cancer model, Anti-cancer drugs 2010, 21(3), 261–269 http://dx.doi.org/10.1097/CAD.0b013e32833410a2CrossrefGoogle Scholar

  • [41] Oh K.S., Song J.Y., Cho S.H., Lee B.S., Kim S.Y., Kim K., Jeon H., Kwon I.C., Yuk S.H., Paclitaxel-loaded Pluronic nanoparticles formed by a temperature-induced phase transition for cancer therapy, J. Control. Releas. 2010; doi:10.1016/j.jconrel.2010.08.021 CrossrefGoogle Scholar

  • [42] C. Mahesh, W. Jane, R.E. Barrett, 2005. Method for preparing submicron particles of paclitaxel. W.O. patent 0466712005 Google Scholar

  • [43] Tomas E., Karel U., Blanka R., Milada S., Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates, Molecules 2008, 13, 360–378 http://dx.doi.org/10.3390/molecules13020360CrossrefGoogle Scholar

  • [44] Leonelli F., Bella A.L., Migneco L.M., Bettolo R.M., Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates, Molecules 2008, 13, 360–378 http://dx.doi.org/10.3390/molecules13020360CrossrefGoogle Scholar

  • [45] B. Martin, C. Ladisav, S. Roman, S. Pavel, 2006. Process for the isolation of paclitaxel. W.O. patent 014356 Google Scholar

  • [46] K.V. Rao, 1995. Method for the isolation and purification of taxol and its natural analogues. U.S. patent 5,475,120 Google Scholar

  • [47] Rao K.V., Taxol and related taxanes. I. Taxanes of Taxus brevifolia bark, Pharm. Res. 1993, 10(4), 521–524 http://dx.doi.org/10.1023/A:1018937700459CrossrefGoogle Scholar

  • [48] Wall M.E., Wani M.C., Camptothecin and Taxol: Discovery to Clinic-Thirteenth Bruce F. Cain Memorial Award Lecture, Cancer Rese. 1995, 55, 753–760 Google Scholar

  • [49] Carlier M.F., Pantaloni D., Taxol Effect on Tubulin Polymerization and Associated Guanosinev 5′-Triphosphate Hydrolysis, Biochemistry 1983, 22, 4814–4822 http://dx.doi.org/10.1021/bi00289a031CrossrefGoogle Scholar

  • [50] Schiff P.B., Fant J., Horwitz S.B., Promotion of microtubule assembly in vitro by taxol, Nature 1979, 277(5698), 665–667 http://dx.doi.org/10.1038/277665a0CrossrefGoogle Scholar

  • [51] Georg G.I., Boge T.C., Cheruvallath Z.S., Clowers S.J., Harriman G.C.B., Hepperle M., Park H., The medical chemistry of taxol. In: Suffness M (ed.), Taxol science and applications., Boca Raton: CRC Press, 1995, pp. 317–375 Google Scholar

  • [52] Nicolaou K.C., Dai W.M., Guy R.K., Chemistry and biology of taxol, Angew. Chem. Int. Edit. 1994, 33, 15–44 http://dx.doi.org/10.1002/anie.199400151CrossrefGoogle Scholar

  • [53] Han Y., Chaudhary A.G., Chordia M.D., Sackett D.L., Ramirez B.P., Kingston D.G.I., Bane S., Interaction of a Fluorescent Derivative of Paclitaxel (Taxol) with Microtubules and Tubulin-Colchicine, Biochemistry 1996, 35, 14173–14183 http://dx.doi.org/10.1021/bi960774lCrossrefGoogle Scholar

  • [54] Horwitz S.B., Mechanizam of action of Taxol, Trends Pharmacol. Sci. 1992, 13(4), 134–136 http://dx.doi.org/10.1016/0165-6147(92)90048-BCrossrefGoogle Scholar

  • [55] Suffness M., Taxol: From Discovery to Therapeutic Use, Ann. Rep. Med. Chem. 1993, 28, 305–314 http://dx.doi.org/10.1016/S0065-7743(08)60902-1CrossrefGoogle Scholar

  • [56] Horwitz S.B., Cohen D., Rao S., Ringel I., Shen H.J., Yang C.P., Taxol: mechanisms of action and resistance, J. Nati. Cancer I 1993, 15, 55–61 Google Scholar

  • [57] Kingston D.G.I., Taxane Anticancer Agents, Chapter 15. USA: American Chemical Society, 1995 Google Scholar

  • [58] Rowinsky E.K., Cazenave L.A., Donehower R.C., Taxol: a novel investigational antimicrotubule agent, J. Nati. Cancer I 1990, 82(15), 1247–1259 http://dx.doi.org/10.1093/jnci/82.15.1247CrossrefGoogle Scholar

  • [59] Kant J., The Chemistry and Pharmacology of Taxol and Its Derivatives, 5 ed. New York, Pharmochemistry Library, Elsevier, 1995 Google Scholar

  • [60] Boge T.C., Himes R.H., Velde D.G.V., Georg G.I., The effect of the aromatic rings of taxol on biological activity and solution conformation: synthesis and evaluation of saturated taxol and taxotere analogues, J. Med. Chem. 1994, 37(20), 3337–3343 http://dx.doi.org/10.1021/jm00046a018CrossrefGoogle Scholar

  • [61] Rowinsky E.K., Donehower R.C., The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics, Pharmacol. Therapeut. 1991, 52(1), 35–84 http://dx.doi.org/10.1016/0163-7258(91)90086-2CrossrefGoogle Scholar

  • [62] Schiff P.B., Horwitz S.B., Taxol stabilizes microtubules in mouse fibroblast cells, PNAS 1980, 77(3), 1561–1565 http://dx.doi.org/10.1073/pnas.77.3.1561CrossrefGoogle Scholar

  • [63] Ding A.H., Porteu F., Sanchez E., Nathan C.F., Shared actions of endotoxin and taxol on TNF receptors and TNF release, Science 1990, 248(4953), 370–372 http://dx.doi.org/10.1126/science.1970196CrossrefGoogle Scholar

  • [64] Manthey C.L., Brandes M.E., Perera P.Y., Vogel S.N., Taxol increases steady-state levels of lipopolysaccharide-inducible genes and protein-tyrosine phosphorylation in murine macrophages, J. Immunol. 1992, 149(7), 2459–2465 Google Scholar

  • [65] Ozcelik B., Turkyilmaz C., Ozgun M.T., Serin I.S., Batukan C., Ozdamar S., Ozturk A. Prevention of paclitaxel and cisplatin induced ovarian damage in rats by a gonadotropin-releasing hormone agonist. Fertil. Steril. 93(5), 1609–1614 Google Scholar

  • [66] Sznitowska M., Klunder M., Placzek M., Paclitaxel Solubility in Aqueous Dispersions and Mixed Micellar Solutions of Lecithin, Chem. Pharm. Bull. 2008, 56(1), 70–74 http://dx.doi.org/10.1248/cpb.56.70CrossrefGoogle Scholar

  • [67] Kim S.C., Jaewon Y., Lee J.W., Seok P.E., Cheol C.S., Sensitive HPLC method for quantitation of paclitaxel (Genexol®) in biological samples with application to preclinical pharmacokinetics and biodistribution, J. Pharmaceut. Biomed. 2005, 39(1–2), 170–176 http://dx.doi.org/10.1016/j.jpba.2005.02.023CrossrefGoogle Scholar

  • [68] Haruo Y., Mihoko N., Mitsuhiro W., Ken’ichiro N., Simultaneous HPLC determination of paclitaxel and verapamil in rat plasma, Chromatography 2005, 26(2), 49–50 Google Scholar

  • [69] Baldrey S.F., Brodie R.R., Morris G.R., Jenkins E.H., Brookes S.T., Comparison of LC-UV and LCMS-MS for the Determination of Taxol, Chromatographia, 2005, 55, S-187–S-192 Google Scholar

About the article

Published Online: 2011-08-09

Published in Print: 2011-10-01


Citation Information: Open Medicine, Volume 6, Issue 5, Pages 527–536, ISSN (Online) 2391-5463, DOI: https://doi.org/10.2478/s11536-011-0074-5.

Export Citation

© 2011 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Praful R Nair, SA Karthick, Kyle R Spinler, Mohammad R Vakili, Afsaneh Lavasanifar, and Dennis E Discher
Nanomedicine, 2016, Volume 11, Number 12, Page 1551

Comments (0)

Please log in or register to comment.
Log in