Bark Of Taxus Brevifolia Research Articles

A Study on Improving Bioavailability of Paclitaxel through different Novel Drug Delivery Approaches

Paclitaxel (PTX) obtained from the bark of Taxus brevifolia (Pacific yew tree) is a well-known potent drug used for treatment of breast, lung and ovarian cancer. PTX is stated to be a novel antimicrotubule agent. PTX acts by assembling the microtubule from tubulin dimmers and stabilizing of microtubules by prevention of polymerization. Thus it affects the cell division of the cancer cells by interrupting the spindle formation. PTX on application in cancer treatment it shows to have low aqueous solubility use of vehicles like Cremophore EL and ethanol, which on application shows hypersensitivity reaction. So to reduce the toxicity due to these vehicles three main dosage forms are seen to be developed for application of PTX in chemotherapy by researchers throughout the world. Namely; Nano-Particle Approaches, Liposomal approach, Solid Dispersion approach. Nanoparticles are utilized for purposes like decreasing toxicity and minimizing adverse effects of drug molecules and enhancing drug release. Liposomes are capable of containing more amount of PTX and are capable of long term stability, toxicity reduction when compared to other dosage form. Solid dispersions are more effective compared to other methods of particle size reduction to improve the drug solubility. So it can be stated that developing dosage forms like these for reduction of toxicity and efficacious application of PTX in chemotherapy is important.

Effect of curcumin and paclitaxel on breast carcinogenesis.

Global cancer burden increased to 14.1 million new cases in 2012; and breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012. Curcumin is the major bioactive ingredient extracted from the rhizome of the plant Curcumalonga (turmeric). Paclitaxel is a microtubule-stabilizing agent originally isolated from the bark of Taxus brevifolia. Curcumin and paclitaxel were evaluated with two human breast cancer cell lines as the luminal MCF-7 and the basal-like MDA-MB-231 that are either positive or negative for hormonal receptors estrogen receptor, progesterone receptor and HER2, respectively. Results indicated that curcumin combined with paclitaxel decreased c-Ha-Ras, Rho-A, p53 and Bcl-xL gene expression in comparison to control and substances alone in MCF-7 cell line. These two substances alone and combined decreased gene expression of Bcl-2 and NF-κB. However, CCND1 increased when both substances were combined in MCF-7 cells. Such substances decreased Bcl-2 and increased Bax protein expression. However, curcumin alone decreased IκBα and Stat-3 gene expression. Paclitaxel alone and combined increased IκBα and Stat-3. Curcumin alone and combined with paclitaxel increased p53, Bid, caspase-3, caspase-8 and Bax gene expression in MDA-MB-231, whereas Bcl-xL decreased such expression in MDA-MB-231 cells. When paclitaxel and curcumin were combined the expression of Bcl-2 protein was decreased. However, either substance alone and combined increased Bax protein expression corroborating the apoptotic effect of these substances. It can be concluded that curcumin may be of considerable value in synergistic therapy of breast cancer reducing the associated toxicity with use of drugs.

Cancer chemopreventive pharmacology of phytochemicals derived from plants of dietary and non-dietary origin: implication for alternative and complementary approaches

The poor survival statistics of the fatal cancer diseases highlight the need for multiple alternative treatment options. An impressive embodiment of evidence shows that naturally occurring herbal products contain a wide variety of phytochemicals that are regarded as effective cancer protective agents, possessing the ability to retard, block or reverse carcinogenesis. These include dietary agents often termed as nutraceuticals and also the components of non-dietary plants. Many studies in different cell lines, animal models and human epidemiological trials suggest a protective role of a large number of medicinal molecules of herbal origin against different types of cancers. The standard chemotherapeutic regime against cancer faces an unequivocal challenge due to the severity of the side-effects and the post therapeutic management of the disease. Cancer control may therefore benefit from the anti-cancer potential of alternative therapies that may include herbal treatment which nonetheless has been an effective curative strategy reported for a number of diseases since ancient times. In congruence of the above idea, it has been observed that in recent years the demand to utilize alternative approaches to the treatment of cancer is escalating. Additionally, the emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of herbal and marine origin. Currently, in the armamentarium of anti-cancer pharmaceuticals there are effective plant-derived drugs such as paclitaxel (a complex taxane diterpene isolated from the bark of Taxus brevifolia) which acts as microtubule disruptor. Further there are plant-based dietary agents such as sulphoraphane (an isothiocyanate derived from cruciferous vegetables) and non-dietary agents such as pomiferin (an isoflavonoid from Maclura pomifera) which strongly mimic chemotherapeutic drugs such as vorinostat (suberoylanilidehydroxamic acid) possessing histone diacetylase inhibition activity. In this review we provide a comprehensive outline of the translational potential of plant-based herbal medicine for complementing the current treatment modalities as an adjuvant or alternative therapy for cancer patients.

Hazel and other sources of paclitaxel and related compounds

Taxanes form a large family of compounds, the most famous of which is paclitaxel, an effective antitumor drug currently used against various cancers. First approved for the treatment of ovarian and breast cancer, it was subsequently endorsed for the treatment of many other cancer pathologies. Originally extracted from the bark of Taxus brevifolia, it has also been found in other Taxus species. Most of the drug for clinical use is currently produced by semi-synthesis, starting from a natural precursor, 10-deacetylbaccatin III recovered from the needles of Taxus baccata. The yield of paclitaxel and its precursors from yew is very low, and is not sufficient to satisfy the commercial requirements. Many attempts have been made to explore new paclitaxel-producing species including microorganisms. However, the availability of paclitaxel and related compounds is still low. The discovery of taxanes in differentiated and undifferentiated tissue of Corylus avellana suggested that the production of these compounds is not a peculiarity of the genus Taxus, giving hope for the future availability of these compounds. Here we review works aimed at exploring new paclitaxel-producing organisms with different ecology to Taxus plants. Particular focus has been placed on highlighting the discovery of taxanes in angiosperm plants. Thus, it is conceivable that, by developing appropriate methodologies, new plant species could be employed for the commercial production of paclitaxel and other antineoplastic compounds.

In vivo biological evaluation of 131I radiolabeled-paclitaxel glucuronide (131I-PAC-G)

Abstract Paclitaxel (PAC) is a natural occurring diterpene alkoloid originally isolated from the bark of Taxus Brevifolia. It is one of the most important antitumor agents for clinical treatment of ovarian, breast non-small cell lung and prostate cancers. It is known that these types of cancer cells have high β-glucuronidase enzyme which can catalyze the hydrolysis of glucuronides. This is why the synthesis compounds which undergo glucuronidation come into question in the imaging and therapy of these cancer cells. The aim of current study is conjugation of glucuronic acid (G) to the starting substance PAC, labeling with 131I and to perform its in vivo biological evaluation. Glucuronic acid derived paclitaxel compound [paclitaxel-glucuronide (PAC-G)] was labeled with 131I using iodogen method. According to thin layer radio chromatography (TLRC) method, the radiochemical yield of 131I-PAC-G was 84.30 ± 7.40% (n=10). The biodistribution of 131I-PAC-G in healthy female and male Wistar Albino rats has been investigated. Imaging studies on male Balb-C mice were performed by using the Kodak FX PRO in vivo Imaging System. The range of the breast/blood, breast/muscle; ovary/blood, ovary/muscle ratios is approximately between 1.29 and 11.34 in 240 min, and between 0.71 and 8.24 in 240 min for female rats. The prostate/blood and prostate/muscle ratio is between 1.94 and 6.95 in 30 min for male rats. All these experimental studies indicate that 131I-PAC-G may potentially be used in breast, ovary and prostate tissues as an imaging agent. Also it is thought that 131I-PAC-G bears a theraphy potential because of the 131I radionuclide and can be improved with further investigations.

In vitro culture of Taxus sp.: strategies to increase cell growth and taxoid production

Interest in Taxus species has increased since paclitaxel, an anticancer drug, was isolated from the bark of Taxus brevifolia (Pacific yew) in the 1960’s. Great effort has been carried out to establish an efficient callus cultures of Taxus species. Culture media must be optimized for each Taxus species, and in general, there is no one method that guarantees success for Taxus cultures. The source of explant, culture medium composition and the growth regulators used appear to affect callus initiation and maintenance. Research effort has focused on obtaining a cell culture that exhibits good growth and a high rate of taxoid accumulation. In this sense, many strategies have been employed to stimulate taxoid production without affecting cell growth. In an attempt to scale-up cell culture, problems such us shear stress, oxygen supply and gas composition have been studied. A more detailed knowledge of the pathway and the fluxes of intermediates towards taxane accumulation will be key factors to obtain cell lines with increased taxane accumulation through metabolic engineering.

Taxanes from Shells and Leaves of Corylus avellana

Paclitaxel is an effective antineoplastic agent originally extracted in low yield from the bark of Taxus brevifolia. Although it was generally considered a particular metabolite of Taxus sp., paclitaxel was recently found in hazel cell cultures. The aim of the present work was to verify whether hazel differentiated tissues could be used as a commercial source of paclitaxel and other taxanes. Thus, shells and leaves of hazel plants were analyzed by ELISA and HPLC-MS. Both shell and leaf extracts contained taxanes. Among these, paclitaxel, 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel were identified and quantified. Hazel extracts also showed biological activity, inhibiting metaphase to anaphase transition in a human tumor cell line. The level of total taxanes in leaves was higher than in shells collected in the same period from the same plants. However, the finding of these compounds in shells, which are considered discarded material and are mass produced by many food industries, is of interest for the future availability of paclitaxel and other antineoplastic compounds.

In vitro cell cultures obtained from different explants of Corylus avellanaproduce Taxol and taxanes

BackgroundTaxol is an effective antineoplastic agent, originally extracted from the bark of Taxus brevifolia with a low yield. Many attempts have been made to produce Taxol by chemical synthesis, semi-synthesis and plant tissue cultures. However, to date, the availability of this compound is not sufficient to satisfy the commercial requirements. The aim of the present work was to produce suspension cell cultures from plants not belonging to Taxus genus and to verify whether they produced Taxol and taxanes. For this purpose different explants of hazel (Corylus avellana species) were used to optimize the protocol for inducing in vitro callus, an undifferentiated tissue from which suspension cell cultures were established.ResultsCalli were successfully induced from stems, leaves and seeds grown in various hormone concentrations and combinations. The most suitable callus to establish suspension cell cultures was obtained from seeds. Media recovered from suspension cell cultures contained taxanes, and showed antiproliferative activity on human tumour cells. Taxol, 10-deacetyltaxol and 10-deacetylbaccatin III were the main taxanes identified. The level of Taxol recovered from the media of hazel cultures was similar to that found in yew cultures. Moreover, the production of taxanes in hazel cell cultures increased when elicitors were used.ConclusionHere we show that hazel cell cultures produce Taxol and taxanes under controlled conditions. This result suggests that hazel possesses the enzymes for Taxol production, which until now was considered to be a pathway particular to Taxus genus. The main benefit of producing taxanes through hazel cell cultures is that hazel is widely available, grows at a much faster rate in vivo, and is easier to cultivate in vitro than yew. In addition, the production of callus directly from hazel seeds shortens the culture time and minimizes the probability of contamination. Therefore, hazel could become a commercial source of Taxol and taxanes, both to be used as new therapeutic agents or as new precursors for Taxol semi-synthesis.

The Future of Organic Synthesis

The extreme structural diversity found in many natural products poses an extraordinary challenge to chemists trying to synthesize these molecules (1). Many natural products are available only in trace quantities from natural sources, making total or partial synthesis a necessity. For example, the drug Taxol, an anticancer natural product, is present only in minute quantities in the bark of Taxus brevifolia. A closely related compound, 10-deacetylbaccatin III, can be extracted from leaf clippings from Taxus baccata with no harm to the tree (2). During studies of the transformation of 10-deacetylbaccatin into Taxol, a compound was synthesized that turned out to be more soluble and twice as active as Taxol itself (3). This compound was developed into the drug Taxotere. Total and partial syntheses of bioactive natural products and derivatives also provide the driving force for the invention of new reactions with ever-increasing levels of efficiency and selectivity.

From taxol to taxol®: The changing identities and ownership of an anti-cancer drug

This paper analyzes the emergence and evolution of taxol, the world's best-selling anti-cancer drug. Over the years taxol has changed its identity, its status as property, and its association with different places (from the old-growth forests of Washington State to the government agencies of Washington, D.C., tolaboratories in France). Taxol is not only a profitable pharmaceutical commodity and a substance injected into women with breast and/or ovarian cancer; it is also a natural product found in the bark of Taxus brevifolia (the Pacific yew, which is native to the North American Pacific Northwest) and a chemical substance that was discovered and brought to the point of commercial production in the public sector. We explore its role in several controversies: the destruction of old-growth forests, public participation in policy making, and the privatization of intellectual property and its effect on the price of drugs.

The Conformations of Taxol in Chloroform

Taxol, isolated from the bark of Taxus breVifolia in the late 1960s, 1 and its semisynthetic Taxotere congener 2 have become the drugs of choice for the treatment of ovarian and breast cancer. 3 The availability of active simplified analogues would facilitate shortened synthetic strategies and potentially bypass neurotoxicity 4 and multidrug resistance. 5 The design of such compounds is hampered by an incomplete understanding of Taxol’s conformation in the bioactive form. Numerous studies have sought to deduce the drug’s three-dimensional state in solution by NMR spectroscopy combined with force-field guided conformational analysis. In both polar and nonpolar solvents, rotamers exhibit hydrophobic collapse 6 between the flexible C-2, C-4, and C-13 side chains, accompanied by variable H2′-C-C-H3′ torsional angles (Table 1). 7,8 Each of the conformational extremes has been proposed as a candidate for the Taxol topology bound to microtubules. 7d,g-j,8b-d

Semi‐synthesis of paclitaxel from naturally occurring glycosidic precursors

AbstractPaclitaxel, an antitumor drug effective on ovarian and breast carcinomas, is currently being produced both by direct isolation from the bark of Taxus brevifolia and by semi‐synthesis from a natural precursor, 10‐deacetyl baccatin III. Although other potential precursors such as 10‐deacetyl paclitaxel‐7‐xyloside were known since 1984, their conversion to paclitaxel could not be achieved because of the lack of suitable methodology for hydrolyzing the xylose residue, compatible with the stability of the compound. A method is described here using periodate, followed by phenylhydrazine, to effect deglycosidation of 10‐deacetyl paclitaxel‐7‐xyloside to form 10‐deacetyl paclitaxel. In addition, by including an intermediate acetylation step before the reaction with phenylhydrazine, “direct” conversion of this xyloside to paclitaxel itself, is described. Because 10‐deacetyl paclitaxel‐7‐xyloside occurs at >0.1% in the bark of Taxus brevifolia, its successful hydrolytic conversion to paclitaxel represents an extremely important reaction for the enhanced availability of this drug.

Supercritical extraction and HPLC analysis of taxol from Taxus brevifolia using nitrous oxide and nitrous oxide + ethanol mixtures

Taxol is an alkaloid which has been found to be exceptionally promising in the treatment of ovarian cancer. The major current sources of the drug are yew species which are in limited supply. As a result, there is a need for improved separation processes to effectively remove the drug from its natural sources. In this study, the separation of taxol from the bark of Taxus brevifolia has been achieved at 320 K and 331 K and at a pressure range of 10.3 to 38.10 MPa using supercritical nitrous oxide and nitrous oxide + ethanol mixtures. The extracts were quantified by high pressure liquid chromatography with photo diode array detection in the UV region. It was found that supercritical nitrous oxide + ethanol mixtures were able to extract most of the taxol present in the bark and that the extractions were more efficient than those using CO 2 + ethanol mixtures.

Synthesis and evaluation of some 10-mono- and 2',10-diesters of 10-deacetylpaclitaxel.

10-Deacetylpaclitaxel, isolated from the bark of Taxus brevifolia, was converted into paclitaxel in one composite step (trimethylsilylation, acetylation, and desilylation) and in an overall yield of 80-85%. A series of 10-monoesters of 10-deacetylpaclitaxel are prepared by protection of the 2'- and 7-hydroxyls with a chloroacetyl group, acylation, and deprotection. Depending on the reaction conditions, the 10-monoesters, either exclusively or accompanied by the 2',10-diesters, are formed. The mono- and diesters were evaluated using the L-1210 cell culture assay. The 10-monoesters were comparable to paclitaxel and more active than the corresponding 2',10-diesters. The 10-[(4-methoxyphenyl)acetyl], 10-(2-nitrobenzoyl), and 10-(phenylacetyl) esters were found to be somewhat more active than paclitaxel.

Taxol® (Paclitaxel)

Taxol® (paclitaxel) has been hailed by many as the most promising new cancer treatment in two decades. The FDA requires that paclitaxel intended for human consumption be obtained only from the bark of Taxus brevifolia, the Pacific yew. As this may become increasingly uneconomical, new strategies must be explored to ensure the continued availability of taxol and related molecules. This article examines the planning that must be engaged in and the contingencies that must be prepared for in this changing arena.

Brevitaxin, a new diterpenolignan from the bark of Taxus brevifolia.

The first terpenolignan, brevitaxin [1], has been isolated from the bark of Taxus brevifolia. Identification was carried out using spectral methods, and the regiochemistry and cytotoxicity of 1 are discussed.

A new large-scale process for taxol and related taxanes from Taxus brevifolia.

In view of the demonstrated antitumor activity of taxol, ready availability of the drug is important. The current isolation methods starting from the bark of Taxus brevifolia involve multiple manipulations, leading to only taxol and in a yield of 0.01%. A new process consisting of a single reverse phase column is introduced here, and the present purpose is to determine its large scale applicability. The chloroform extractable fraction of the bark of T. brevifolia is applied directly on to a C-18 bonded silica column in 25% acetonitrile/water, with elution using a step gradient: 30-50% acetonitrile/water. On standing, eight different taxanes, including taxol, crystallize out directly from different fractions. The crystals are filtered and purified further by recrystallization. Taxol and four other taxanes are purified this way. The other three require a short silica column. Taxol is freed from cephalomannine by selective ozonolysis. The large scale process gave taxol (0.04%), 10-deacetylbaccatin III (0.02%), 10-deacetyl taxol-7-xyloside (0.1%), 10-deacetyl taxol-C-7-xyloside (0.04%), 10-deacetyl cephalomannine-7-xyloside (0.006%), taxol-7-xyloside (0.008%), 10-deacetyl taxol (0.008%) and cephalomannine (0.004%). Processing of the needles of T. brevifolia gave brevifoliol (0.17%), and that of the wood, 10-deacetyl taxol-C-7-xyloside (0.01%) and 10-deacetyl taxol-C. The reverse phase column process is simpler (one column, direct crystallization), more efficient (eight taxanes obtained simultaneously) and also gives higher yields.

The stimulation of taxol production in Taxus brevifolia by various growth retardants

We have shown that chlorocholine chloride (CCC), succinic acid, 2,2-dimethylhydrazide (Alar ®) and tetramethylammonium bromide (TMAB) stimulate [ 14C]acetate incorporation into taxol in intact pieces of the inner bark of Taxus brevifolia (Pacific yew). Both CCC and Alar also stimulated taxol production in yew logs as measured by the incorporation of [1- 14C]acetate into [ 14C]taxol. An increase in taxol accumulation also occured in silica gel placed under flaps of yew trees in the forest treated with these two compounds. CCC also caused an increase, in an 8-week treatment period, of recoverable taxol from Pacific yew bark in a forest setting. CCC, alar and TMAB are all known as growth retardants, but may cause an effect on taxol biosynthesis via an inhibition of sterol biosynthesis.

Intramolecular acyl migrations in taxanes from Taxus brevifolia

Two new taxane epoxides were isolated from the bark of Taxus brevifolia and their structures were established as 1β,9α-dihydroxy-4β,20-epoxy-2α,5α,7β,10β,13α-pentaacetoxy-tax-11-ene and 1β,7β-dihydroxy-4β,20-epoxy-2α,5α,9α,10β,13α-pentaacetoxy-tax-11-ene. These two compounds were found to readily isomerize via acyl migration upon standing in CDCl 3 solution and represent the first example of intramolecular transesterification in this large family of taxane metabolites.

Phase II Study of Taxol in Patients With Untreated Advanced Non-Small-Cell Lung Cancer

Taxol, a complex plant product (a diterpene) extracted from the bark of Taxus brevifolia, has demonstrated substantial anticancer activity in ovarian and breast cancers, malignant melanoma, and acute myelogenous leukemia. Due to allergic reactions in phase I and early phase II studies, use of a 24-hour infusion of taxol with prophylactic dexamethasone, diphenhydramine, and cimetidine has been recommended. In this phase II study, we attempted to determine the efficacy and toxicity of taxol in patients with advanced (stage IIIB or IV) non-small-cell lung cancer who had never received chemotherapy. Patients were not excluded because of prior surgery or because of radiotherapy administered more than 4 weeks before study entry. Taxol was administered in the hospital at a dose of 200 mg/m2 as an intravenous infusion over 24 hours and repeated every 3 weeks, provided that patients had recovered from any toxic effects. Dexamethasone, cimetidine, and diphenhydramine were given before chemotherapy to prevent hypersensitivity reactions. Therapy was continued for at least two courses unless there was rapid disease progression and for at least three courses if no change was observed and no grade 3 or 4 toxic effects occurred. Treatment was continued for six more courses after maximum response or for two more courses after complete remission but was discontinued if disease progressed. Of the 27 patients entered in the study, 25 were assessable for toxic effects and response. One patient had an allergic reaction that was not life threatening. The overall response rate was 24% (one complete response and five partial responses). An additional seven patients (28%) had minor response. Granulocytopenia was the dose-limiting toxic effect, and neutropenic fever occurred in eight of 118 courses. One additional patient developed neutropenic sepsis with hypotension but recovered with intensive treatment. Taxol appears to have activity against non-small-cell carcinoma of the lung. A phase II study combining taxol, etoposide, and cisplatin and using hematopoietic stimulating factors is now proposed. The optimal dose for combination chemotherapy has yet to be determined. An important consideration is potential cardiac effects of taxol with other drugs.