EP0642586A4 - TISSUS DE -i(TAXUS) MIS EN CULTURE UTILISE COMME SOURCE DE TAXOL, TAXANES ET AUTRES NOUVEAUX COMPOSES ANTITUMORAUX/ANTIVIRAUX APPARANTES. - Google Patents

TISSUS DE -i(TAXUS) MIS EN CULTURE UTILISE COMME SOURCE DE TAXOL, TAXANES ET AUTRES NOUVEAUX COMPOSES ANTITUMORAUX/ANTIVIRAUX APPARANTES.

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Publication number
EP0642586A4
EP0642586A4 EP93911220A EP93911220A EP0642586A4 EP 0642586 A4 EP0642586 A4 EP 0642586A4 EP 93911220 A EP93911220 A EP 93911220A EP 93911220 A EP93911220 A EP 93911220A EP 0642586 A4 EP0642586 A4 EP 0642586A4
Authority
EP
European Patent Office
Prior art keywords
taxol
taxus
culture
roots
root
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93911220A
Other languages
German (de)
English (en)
Other versions
EP0642586A1 (fr
Inventor
Richard N Arteca
Enaksha Wickremesinhe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Penn State Research Foundation
Original Assignee
Penn State Research Foundation
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Filing date
Publication date
Application filed by Penn State Research Foundation filed Critical Penn State Research Foundation
Publication of EP0642586A1 publication Critical patent/EP0642586A1/fr
Publication of EP0642586A4 publication Critical patent/EP0642586A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/04—Plant cells or tissues
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms

Definitions

  • Taxol is a potent inhibitor of cell replication that acts as an antimitotic agent, blocking cells in the G2/M phase of the cell (Schiff & Horowitz, 1980; Horowitz et al . , 1986). It is unique in its ability to bind stoichiometrically to polymerized tubulin both in vitro and in vivo, and to induce the assembly of tubulin to form calcium-stable aggregated microtubule structures. These structures resist depoly erization by dilution, calcium ions, cold and a number of microtubule-disrupting drugs.
  • Microtubules assemble tubulin in the absence of exogenous guanosine 5 ' -triphosphate or microtubule-associated proteins at low temperatures (Schiff & Horowitz, 1980; ParnessS and Horowitz, 1981; Howard & Timashef , 1988) .
  • Taxol exhibits activity against the KB cancer cell line used to screen for potential chemotherapeutic agents in tissue culture. During preclinical evaluation studies, taxol has been shown to have activity against both urine solid tumor lines and leukemic cell lines (Wani et al . , 1971; Suffness & Cordell, 1985; Donehower et al. , 1987) .
  • taxol has been extracted from a natural source
  • extraction has been extremely painstaking and, because the compounds of interest are found at extremely low concentrations in plants (0.02% dry weight basis), is associated with yields that are grossly inadequate for both present and anticipated needs.
  • initial extracts are contaminated with pigments, highly hydroponic cuticular substances, waxes and the like, which must be removed.
  • taxol is generally meant to include compounds which are structurally related to taxol and are defined to include precursors of taxol in biochemical pathways which are capable of producing taxol, to intermediates of those pathways, and to derivatives and secondary metabolites of taxol (10-deacetyl baccatin III, 7-epi-10-deacetyl baccatin III, baccatin III, 7-epi baccatin III, 9-dihydro-13-acetyl baccatin III, cephalomannine, 10-deacetyl taxol, 7-epilO-deacetyl taxol, 7-epi taxol) and other known and unknown natural derivatives of these compounds and related taxanes resulting in taxol production and/or the production of novel antitumor/antivira1 compounds.
  • Taxol-like activity refers to compositions which show positive results in at least one test predictive of effective chemotherapy: a microtubul
  • Stable cultures are cultures that maintain a taxol production level after repeated subcultures.
  • Long-term cultures re those that remain stable for at lease one year, preferably two or more years.
  • Cultures produced by methods of the present invention have remained stable for up to seven years.
  • Some of the cell lines are habituated, that is, they do not require plant hormones as supplements to the nutrient culture medium for long-term maintenance.
  • the cell lines established by use of the methods of the present invention are capable of producing taxol, and taxol- related compounds. These cell lines offer a rapidly reproducible, continuously-available source for the production of taxol and taxol-related compounds.
  • the general tissue source is plants of the genus Taxus.
  • Various species from which taxol may be isolated include T. brevifolia Nutt, T. Jaccata, T. cuspidata, T. canadensis cv. Capitata, T. media cv. Densiformis, and T. media cv. Hicksii.
  • Preferred sources for explants used to produce taxol- expressing cultures are those plants from which the amount of taxol that may be extracted directly is high when compared with amounts extracted from other species by comparable methods from comparable amounts of starting material.
  • T. -media more particularly T. media cv. Hicksii, for example, is a more preferred source than T.
  • Friability is another selection criterion. This is determined by observing a crumbly, fragile texture of the callus. Another factor which indicates samples that are likely to result in successful cell lines for purposes of the present invention is relative growth rate of the callus cells. Initially, all callus are slow growing, taking about 2-4 months to double. Preferable doubling times are from about 5-16 days. Subculturing was performed at intervals of about 4-6 weeks, although the interval may be shorter or longer depending on the health of the callus, as indicated by color, and by the size of the callus after growth.
  • Cell lines are suitable as sources to grow in bioreactors to produce large quantities of taxol, and taxol-related compounds. Some of these compositions are found in the culture medium and may be obtained by collecting the medium. Utilizing different bioreactor designs, the secondary metabolites found in solution may be easily removed from the solution utilizing exchange resins which extract only the desired secondary metabolites from the solution and not the media supplements required for culture growth. Other compositions are produced and retained intracellularly and must be extracted from the cells.
  • Roots cultured in accordance with the present invention are a continuous source of taxol because they can be maintained indefinitely, under aseptic conditions and retain their ability to produce taxol, active derivatives and precursors of taxol. They grow well in large scale bioreactors and can be cryopreserved. Taxol production ability is retained after cryopreservation or storage at 4-10"C.
  • Roots from a wide range of Taxus species and cultivars grown under optimized conditions described herein are elicited both in vivo and in vitro with biotic (ie. fungal extracts) and abiotic elicitors (i.e. heavy metals) , plant growth regulators, precursors and/or intermediates in the taxol biochemical pathway (i.e. acetate, mevalonic acid) resulting in an increase taxol and related taxanes and/or novel antitumor compounds.
  • biotic ie. fungal extracts
  • abiotic elicitors i.e. heavy metals
  • plant growth regulators i.e. acetate, mevalonic acid
  • An "active" composition is one that is capable of giving positive results in a microtubule stabilizing assay, a cancer model assay, a clinical trial, or any combination of these tests.
  • Elicitation techniques techniques applied to a cell culture which increase the yield of taxol or taxol-related compounds that are produced by the culture; the mechanism of this empiric effect may be immunological, that is, the cells may mount a defense against foreign agents by producing taxol.
  • Abiotic examples include salts of heavy metals,vanadate; lead and mercury.
  • Secondary metabolite a metabolite that is not part of the primary metabolic network of the cells. Secondary metabolites are usually present only in cells that specialize in some way (e.g. defense) .
  • Sparging forcing (bubbling) air through a liquid medium.
  • FIGURE 3 HPLC profile of a root culture of T. media cv. Hickii
  • the cultures of the present invention are induced from the Taxus species including: T. brevifolia , T. canadensis, T. chinensi ⁇ , T. floridana, T. globosa, T. sumatrana, T. yunnanensis and from different cultivars of T. baccata . T. cuspidata and T. media and others from the genus Taxus .
  • glucose, fructose or sucrose 40-80 g/1 is preferred to the standard 20-30 g/1 of sucrose in nutrient medium.
  • NAA to 1 mg kinetin.
  • auxins NAA (at a range of 1.0-5.0 mg/1), 2,4-D (at a range of 0.1-2.5 mg/1) or IBA (indole butyric acid, at a range of 1.0-5.0 mg/1) are suitable.
  • 1 ppm ppm
  • 2,4-D and 0.2 ppm kinetin are added to the cultures, alone or in combination with Gelrite or agar as gelling agents.
  • Explants are placed in tissue culture vessels, which can be petri dishes containing medium gelled with Gelrite, at about a 2 g/1 concentration. Prior to being dispensed into sterile petri dishes, the medium may be sterilized, for example, autoclaved at 121 * C for about 15 minutes.
  • Roots which are actively growing after 2-4 weeks are selected for transfer. Callus formation is determined when globular aggregates of undifferentiated cells are observed. This typically occurs on 90% of the explants within about 2-4 weeks. Subculturing was initially performed at 4-6 week intervals. The doubling is initially very slow, however, with time in culture the doubling rate of selected clones increases to 5-16 days allowing for subculture every 2-3 weeks depending on the clone. After establishing stable callus lines for each of the species/cultivars previously mentioned, callus is transferred to root inducing media where it generally takes 4-6 weeks to initiate roots.
  • the optimum culture conditions for the selected subclones are then determined by a multivariate analysis of factors which are likely to effect culture growth: presence or absence of light, gas composition, temperature, pH, medium supplements including plant hormones and sugars. After stable culture growth is achieved, the root cultures are kept in maintenance medium. For some of the root cultures, habituation occurs, that is, the cultures are maintained without the need for hormonal supplements.
  • Taxus plants are relatively easy to propagate from cuttings, however, methods vary. Taxus cuttings are highly topophytic and will maintain the growth habit they exhibit on the parent plant. In one example, cuttings were collected from September through December after a hard frost. These are roots from dormant plants, which may explain high yields of taxol rom root cultures. Metabolic root activity may be higher during plant dormancy. Cuttings taken after a frost typically root more readily than cuttings without a frost.
  • the surface sterilized stems were cut into sections under aseptic conditions and placed on Gamborg's B5 media plus and minus 2,4-D, kinetin or 2,4-D plus kinetin in the light and dark at 25 * C.
  • Undifferentiated callus tissue was initially slow growing, however, through many subcultures a friable yellowish colored cell line designated Gl with stable growth characteristics was obtained. This cell line grows on Gamborg's B5 media (Table II) in the dark at 25 * C without the supply of any exogenous hormones.
  • Authentic taxol and cephalomannine have retention times of 31 and 25 minutes, respectively.
  • Callus samples such as CR-1 have retention times corresponding to authentic taxol and cephalomannine, however, suspension lines such as S2 have peaks which are shifted, eluting at 32 and 25 minutes respectively. This shift in retention times led to difficulty in purification of these compounds from suspension lines. This is not a problem with root cultures.
  • LG3 was subcultured on different hormone regimes consisting of various combinations of 2-isopentyladenine and indole-3-butyric acid (0.1, 1.0 and 5.0 ppm) .
  • the cell line is capable of secreting taxol, active derivatives of taxol, cephalomannine, baccatin and other precursors of taxol into the growth medium.
  • Taxol, cephalomannine and baccatin were identified in each of the Taxus media cv. Hicksii cell lines CRl, S3, SRI, and LG3 using HPLC analysis (see Materials and Methods) . This was accomplished by making comparisons of retention times between plant samples and authentic standards. Taxol activity was also confirmed by showing that extracts have the ability to stabilize microtubules in the same manner as authentic taxol. The third line of evidence that taxol was contained in the cell lines was by purifying taxol on HPLC and identifying taxol this purified sample by nuclear magnetic resonance analysis. Derivatives of taxol and additional precursors were also identified by HPLC in each of cell lines.
  • the root cultures are maintained on membrane rafts placed inside Magenta GA-7 vessels and in shaker cultures are maintained in 1L shaker culture flasks and subcultured every 2 weeks.
  • Cryopreservation for long term storage of root cultures during the log phase of growth was accomplished by using standard cryopreservation methods using sorbitol and DMSO as the cryoprotectant. Cryopreservation was shown to have great potential for long term preservation of roots whose biosynthetic capacity for synthesis and accumulation of secondary metabolites remain intact following removal from storage.
  • Aseptic normal and "hairy roots” are grown under the following conditions: on maintenance medium containing hormones for normal roots, and without hormones for "hairy roots," 25°C, pH 5.6, 21% 0 2 on the remainder air, and kept in darkness, are used as a source of root tips for multivariate analysis of growth/taxane production.
  • Several root tips are transferred to Gamborgs B5, Murashige and Skoog, McCown's Woody plant liquid media, and aerated.
  • the growth of the roots are suitable in a "nutrient film system.”
  • This system has nutrient solution flowing over the membrane which supports the roots and is recirculated. Nutrients can be added as needed by measuring conductivity, and the presence of taxol, taxol derivatives and precursors in the medium can be assayed by sampling from the solution in line.
  • This scale-up system is analogous to the growth of the roots on membrane rafts.
  • This system can also be optimized by having the nutrient medium sprayed onto the roots intermittently through a system consisting of a nozzle, a peristaltic pump and a timer, thereby supplying the nutrients more uniformly to the entire root mass and also by increasing nutrient uptake, efficiency, andminimizing nutrient use.
  • growth of the top portion of the plant is slowed by applying growth retardants such as Cycocel to the foliage at concentrations ranging from 500 to 1000 ppm, and then evaluating growth rates and taxane production.
  • growth retardants such as Cycocel
  • new reactors may be designed.
  • the proper adjustment of environmental conditions such as gas composition, dissolved oxygen, rate of sparging and speed of agitation, temperature, light, pH of the growth medium, nutrients and organic supplements, removal of secondary products from the medium through the use of resins and elicitation are required to optimize the systems.
  • microtubule stabilizing bioassay The microtubule stabilizing bioassay is used to screen for the ability of a composition to stabilize the formation of microtubules. There is a direct, predictive correlation between results in the microtubule bioassay and the chemotherapeutic action of a composition in cancer model assays. Therefore, the microtubule stabilizing bioassay is recognized by those of skill in the art as a screening test for effective chemotherapeutic agents for further clinical trials.
  • MT proteins neuronal microtubule (MT) proteins are prepared according to the methods of Shelanski et al. (1973) using fresh calf brains. Endogenous microtubule-associated proteins (MAPs) are removed from MT proteins which have been cycled one time, by cycling 4 times in the presence of 1 M glutamate (Hamel and Lin, 1981) . After completion of the cycling, the last tubulin pellet obtained is solubilized in cold PM buffer and is further purified by phosphocellulose chromatography according to Weingarten et al . (1975).
  • MAPs microtubule-associated proteins
  • Taxus stem explants Approximately 90% of the Taxus stem explants showed callus induction after about 2-4 weeks of initiation. Yellow colored callus were selected, separated from the explant, and subcultured. Callus characteristically show initial slow growth, only doubling in about 3-6 months or longer. Another difficulty to be overcome is that most callus turn a brownish color within 1-3 weeks after subculture, and eventually die. Red-colored exudates were another sign of impending cell death.
  • Roots / root cultures were harvested, freeze-dried, and extracted with 1:1 mix of ethanol and methylene chloride by homogenizing in an Omni-mix homogenizer (Omni International, Waterbury, Connecticut) followed by sonication for 15 minutes.
  • the extract was filtered through a Whatmann # 1 filter paper and the filtrate was concentrated to dryness in vacuo.
  • the residue was then partitioned between methylene chloride and water and the methylene chloride fraction was concentrated to dryness under a stream of nitrogen.
  • the final pellet/residue was then resuspended in acidic methanol (0.1% acetic acid), and filtered through a 0.2 micron nylon filter for high performance liquid chromatography (HPLC) analysis.
  • HPLC high performance liquid chromatography
  • Duplicate injections were made from every sample and the average of the two peak areas was used to quantify taxol and cephalomannine.
  • a linearity curve was established for all the major taxanes by injecting amounts of authentic standards ranging from 0.001 to 10 mg per injection. Peaks for taxol were confirmed by collecting them and running then in the microtubule stabilizing bioassay and NMR analysis.
  • Taxol an important new drug in the management of epithelial ovarian cancer. Yale J. Biol. Med. 64: 583-590.
  • Taxol A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Annals of Internal Medicine 111:273-279 (1989).
  • Taxol Twenty tears later, the story unfolds. J. Nat. Cancer Inst. 83, 1778-1781. Schiff, P.B. and S.B. Horowitz. Taxol stabilizes microtubules in mouse fibroblast cells. Proc. Nat. Acad. Sci. 77(3) :1561-1565 (1980).
  • Taxol a novel antileukemic and antitumor agent from Taxus brevifolia. J. American Chemical society 93:2325-2327 (1971).
  • Kirschner A protein factor essential for microtubule assembly. Proc. Nat. Acad. Sci. USA, 72:1858-1862 (1975) .
  • Wickremesinhe, E.R.M. and Arteca, R.N. 1991a Production of taxol in callus and cell suspension cultures of Taxus media 'Hicksii". In Vitro, 27, 109A (abstract) . Wickremesinhe, E.R.M & Arteca, R.N. (1993b) Callus induction from stem explants of Taxus. Submitted to Plant Cell Reports. Wickremesinhe, E.R.M. and Arteca, R.N. 1993a. Establishment of fast-growing callus and root cultures of Cephalotaxus harringtonia. Plant Cell Rep. 12, 80-83.
  • Taxus spp. needles contain amounts of taxol comparable to the bark of Taxus brevifolia: analysis and isolation. J. Natural Products 53:1249-1255 (1990) .

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Botany (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Epoxy Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Breeding Of Plants And Reproduction By Means Of Culturing (AREA)

Abstract

On a mis au point des procédés de culture fructueux permettant d'obtenir des cultures tissulaires stables à long terme dérivées d'explants de Taxus et de racines cultivées en culture hydroponique. Ces cultures offrent une source reproductible rapidement et disponible continûment de production de taxol purifié et de composés apparantés au taxol. Les procédés de culture comprennent la culture tissulaire et la culture hydroponique in vitro. Les cultures sont amorcées au moyen de tissus de tiges ou de racines de Taxus ou à partir de racines mises en culture hydroponique. La production de Taxol peut être élevée à l'échelle commerciale au moyen de bioréacteurs. On a mis au point des méthodes de triage des espèces de culture de Taxus qui constituent des sources de taxol et de composés apparentés au taxol. De plus, pour obtenir les mêmes compositions que celles extraites à l'heure actuelle directement à partir d'ifs, on a purifié de nouvelles compositions présentant une activité analogue à celle du taxol à partir des nouvelles sources de Taxus, offrant de nouveaux horizons pour le développement d'agents chimiothérapeutiques.
EP93911220A 1992-05-21 1993-05-11 TISSUS DE -i(TAXUS) MIS EN CULTURE UTILISE COMME SOURCE DE TAXOL, TAXANES ET AUTRES NOUVEAUX COMPOSES ANTITUMORAUX/ANTIVIRAUX APPARANTES. Withdrawn EP0642586A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US88661992A 1992-05-21 1992-05-21
US886619 1992-05-21
PCT/US1993/004424 WO1993023555A1 (fr) 1992-05-21 1993-05-11 Tissus de taxus mis en culture utilise comme source de taxol, taxanes et autres nouveaux composes antitumoraux/antiviraux apparantes

Publications (2)

Publication Number Publication Date
EP0642586A1 EP0642586A1 (fr) 1995-03-15
EP0642586A4 true EP0642586A4 (fr) 1995-11-29

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EP93911220A Withdrawn EP0642586A4 (fr) 1992-05-21 1993-05-11 TISSUS DE -i(TAXUS) MIS EN CULTURE UTILISE COMME SOURCE DE TAXOL, TAXANES ET AUTRES NOUVEAUX COMPOSES ANTITUMORAUX/ANTIVIRAUX APPARANTES.

Country Status (5)

Country Link
EP (1) EP0642586A4 (fr)
JP (1) JPH08500973A (fr)
AU (1) AU4242993A (fr)
CA (1) CA2136213A1 (fr)
WO (1) WO1993023555A1 (fr)

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WO1993023555A1 (fr) 1993-11-25

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