EP1572191A1 - Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains - Google Patents

Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains

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Publication number
EP1572191A1
EP1572191A1 EP02781652A EP02781652A EP1572191A1 EP 1572191 A1 EP1572191 A1 EP 1572191A1 EP 02781652 A EP02781652 A EP 02781652A EP 02781652 A EP02781652 A EP 02781652A EP 1572191 A1 EP1572191 A1 EP 1572191A1
Authority
EP
European Patent Office
Prior art keywords
brevifoliol
pharmaceutically acceptable
acceptable carrier
formula
chemotherapeutic treatment
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Withdrawn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
EP02781652A
Other languages
German (de)
English (en)
Inventor
S.P.S. Central Ins. Med. & Arom. Plants KHANUJA
RSK C. Ins. Med. & Arom. Plants TIRUPADIRIPULIYUR
A. Central Ins. Med. & Arom. Plants GARG
R.K. Central Ins. Med. & Arom. Plants MISHRA
SK Central Ins. Med. & Arom. Plants CHATTOPADHYAY
S. Central Ins. Med. & Arom. Plants SRIVASTAVA
A.S. Central Ins. Med. & Arom. Plants NEGI
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.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Priority claimed from PCT/IB2002/005399 external-priority patent/WO2004054569A1/fr
Publication of EP1572191A1 publication Critical patent/EP1572191A1/fr
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to a method for the chemotherapeutic treatment of human beings using brevifoliol. More particularly, the present invention relates to the use of brevifoliol for the treatment human cancer lines. The present invention also relates to the bioactivity testing of taxanes from the leaves of Himalayan Yew tree Taxus wallichiana against human cancer cell lines grown in- vitro and subsequent identification of brevifoliol [1] as anticancer agent useful in the treatment of various types of cancer in humans. The present invention also relates to a pharmaceutical composition containing brevifoliol and a pharmaceutically acceptable carrier for the chemotherapeutic treatment of human beings.
  • Taxus brevifolia Nutt. was described by Wani M.C. et al (in 1971, J.Am.Chem.Soc. 93, 2325- 2327).
  • This compound named taxol (also known in the literature as paclitaxel) demonstrated moderate in vivo activity against the P-388, P-1534, and L-1210 murine leukaemia, the Walker 256 carcino-sarcoma, sarcoma 180, and Lewis lung tumor test systems. Taxol has a wide spectrum of anticancer activity. It has been approved by the Food and Drug Administration of United States in 1992 for the treatment of ovarian cancer and again in 1994 for the treatment of breast cancers.
  • taxol has garnered support as an anticancer agent, culminating in recent FDA approval of its use against breast and ovarian cancers.
  • Taxol shows promise against refractory breast and ovarian cancers, which are difficult to treat and which are responsible for the deaths of 60,000 women every year (Chemical &Engineering News 1991, (Sept.), 11-18).
  • antimicrotubule agents which block microtubule production, taxol promotes tubulin polymerisation and stabilizes microtubules against depolymerization (Schiff P.B., et al. 1979, Nature 277, 665-667).
  • Microtubules are important subcellular target for chemotherapeutic agents.
  • Antimicrotubule agents including the Ninca (Catharanthus) alkaloids, are extremely potent, requiring only a few molecules to disrupt the microtubular structure of cancer cells. The discovery of a new compound targeting these structures is of particular importance.
  • Himalayan yew has a remarkable history of medicinal uses.
  • the leaves of the Himalayan yew are used for treatment of hysteria, epilepsy, nervousness and as a lithic in calculus complaints while its non-poisonous fleshy arils have carminative, expectorant and stomachic properties (The Wealth of India (1976), p.132-134).
  • Himalayan yew (Taxus wallichiana) also contains the potent anticancer drug taxol and its important precursor 10-deacetyl baccatin III (DAB).
  • the aim of present invention was to isolate different types of taxanes other than taxol, from the leaves commonly called 'needles' of Taxus wallichiana and evaluate their anticancer potential.
  • a taxane brevifoliol [1] was identified which showed promising anticancer activity against in- vitro grown human cancer cell lines.
  • the main object of the invention is to provide a composition for the chemotherapeutic treatment of human beings.
  • the present invention provides bioactivity testing of various taxanes isolated from leaves of Himalayan Yew tree Taxus wallichiana against human cancer cell lines grown in- vitro and subsequent identification of brevifoliol [1] as anticancer agent useful in the treatment of various types of cancer such as ovarian (PA-1), colon (Caco-2), breast (MCF-7) and oral (KB-403) cancer cells where the IC90 values are comparatively similar or even less than that of standard drug 'taxol'.
  • Brevifoliol is used as a cancer chemotherapeutic agent.
  • the present invention provides a composition for chemotherapeutic treatment of human beings, comprising a pharmaceutically effective amount of brevifoliol of the formula 1 and a pharmaceutically acceptable carrier.
  • the amount of brevifoliol is in the range of 0.004 to 20 ⁇ g/ml.
  • the present invention also provides a method for the chemotherapeutic treatment of human beings comprising administering to a patient suffering from cancer, a therapeutically effective amount of brevifoliol of the formula 1
  • Formula 1 along with a pharmaceutically acceptable carrier.
  • the concentration of brevifoliol is in the range of 0.004 to 20 ⁇ g/ml.
  • the pharmaceutically acceptable carrier does not interfere with the activity of brevifoliol.
  • the chemotherapeutic treatment is limited to ovarian, colon, breast and oral cancers.
  • the invention also provides a method for treatment of human cancer lines comprising administering to a patient a therapeutically effective amount of brevifoliol of the formula 1
  • Formula 1 along with a pharmaceutically acceptable carrier.
  • the concentration of brevifoliol is in the range of 0.004 to 20 ⁇ g/ml.
  • the pharmaceutically acceptable carrier does not interfere with the activity of brevifoliol.
  • the human cancer lines are selected from the group consisting of ovarian (PA-1), colon (Caco-2), breast (MCF-7) and oral (KB-403) cancer cells.
  • the present invention also provides for the use of brevifoliol of the formula 1
  • Formula 1 along with a pharmaceutically acceptable carrier for the chemotherapeutic treatment of human beings.
  • the concentration of brevifoliol is in the range of 0.004 to 20 ⁇ g/ml.
  • the pharmaceutically acceptable carrier does not interfere with the activity of brevifoliol.
  • the chemotherapeutic treatment is limited to ovarian, colon, breast and oral cancers.
  • the invention also provides for the use of brevifoliol of formula 1
  • Formula 1 along with a pharmaceutically acceptable carrier for chemotherapeutic treatment of human beings.
  • the concentration of brevifoliol is in the range of 0.004 to 20 ⁇ g/ml.
  • the pharmaceutically acceptable carrier does not interfere with the activity of brevifoliol.
  • the human cancer lines are selected from the group consisting of ovarian (PA-1), colon (Caco-2), breast (MCF-7) and oral (KB-403) cancer cells. Detailed description of the invention
  • the IC 90 data obtained by the MTT assay may overestimate the cell killing activity of a compound.
  • the clonogenic assay for tumor cells which determines the actual cell death was performed to determine the cytotoxic potential of test compounds.
  • Persons skilled in the art of anti-cancer drug discovery can perform both these assays.
  • brevifoliol was highly inhibitory to ovarian (PA-1), colon (Caco-2), breast (MCF-7) and oral (KB-403) cancer cells where the IC90 values were comparatively similar or even less than that of standard drug 'taxol'.
  • PA-1 ovarian
  • Caco-2 colon
  • MCF-7 breast
  • KB-403 oral cancer cells where the IC90 values were comparatively similar or even less than that of standard drug 'taxol'.
  • brevifoliol can be used as cancer chemotherapeutic agent.
  • Brevifoliol was first isolated from the leaves (also referred as 'needles') of the plant Taxus brevifolia (Baka et al Phytochemistry 30, p.1613-1614; 1991). The process of its isolation involved extracting the fresh leaves of Taxus wallichiana with ethyl alcohol to get an extract. The crude extract after concentration was diluted with water and partitioned between hexane, chloroform and ethyl acetate sequentially. The chloroform extract upon concentration yielded a dark brown residue. The resultant residue was subjected to column chromatography over silica gel and eluted with chloroform and chloroform-methanol gradient. Six fractions were collected and brevifoliol was isolated from fraction five by rechromatography over silica gel and eluting with hexane-ethyl acetate gradient.
  • Brevifoliol has been isolated from other species of Taxus including the Himalayan yew tree Taxus wallichiana that is available in India. Recently, the structure of brevifoliol has been revised and it was shown to belong to 11 (15-1) abeo taxoid bicyclic skeleton of formula [1].
  • brevifoliol was also isolated from the leaves of the plant following a process which involved extracting the dried and crushed needles of Taxus wallichiana with methanol for 72 hours and the extract was concentrated in vacuo. The concentrate was diluted with water and extracted with hexane and chloroform respectively. Concentration of the chloroform phase under vacuum left a residue, which was separated by column chromatography over silica gel.
  • Cytotoxicity testing in vitro was done by the method of Woerdenbag et al.,1993; J.NatProd. 56 (6): 849-856). 2x10 3 cells/well were incubated in the 5% CO 2 incubator for 24h to enable them to adhere properly to the 96 well polysterene microplate (Grenier, Germany). Test compounds dissolved in 100% DMSO (Merck,Germany) in at least five doses were added and left for 6h after which the compound plus media was replaced with fresh media and the cells were incubated for another 48h in the CO 2 incubator at 37°C. The concentration of DMSO used in our experiments never exceeded 1.25%, which was found to be non-toxic to cells.
  • IC 90 is the concentration ⁇ g/mL required for 90% inhibition of cell growth as compared to that of untreated control.
  • the results described in Table 2 indicate that brevifoliol is active against all cancer cell lines except liver cancer (WRL-68).
  • Table 2 Cytotoxic properties (IC 90 in ⁇ g/mL) of various taxanes isolated from T.wallichiana against human cancer cells.
  • the clonogenic assay for tumor cells which determines the actual cell death was performed to determine the cytotoxic potential of test compounds.
  • the principle of clonogenic assay is to investigate the ability of an individual cell to form a colony on a soft agar plate containing various concentrations of test compounds.
  • IC 90 concentration of test compound resulting in 90 % of the control (untreated) colonies was denoted as IC 90 and was used as a parameter for cytotoxicity.
  • the assay was performed as described previously except that the test compounds were added into the top soft agar and the cells were plated out to form colonies.
  • Anthracycline derivative doxorubiciti and microtubule depolymerization inhibitor paclitaxel both established anticancer agents were included as standard reference drugs.
  • Table 3 Cytotoxic properties (IC 90 in ⁇ g/mL) of various taxanes isolated from T.wallichiana against human cancer cells.
  • Brevifoliol was crystallized from petroleum ether-acetone mixture as needles. Brevifoliol, mp 200-201°C, ]D -25°C (C 1, MeOH) was characterized on the basis of its reported spectral data and by direct comparison with an authentic sample (Chattopadhyay, S.K. et al , Indian J. Chemistry 35B, 175-177 (1996)). The reaction mechanism is given below:

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  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la bioactivité de taxanes isolées à partir des feuilles de l'if commun de l'Himalaya Taxus wallichiana contre des lignées cellulaires cancéreuses humaines cultivées in vitro, et l'identification subséquente de brévifoliol (1) comme agent anticancéreux destiné au traitement de divers types de cancer chez les humains.
EP02781652A 2002-12-16 2002-12-16 Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains Withdrawn EP1572191A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2002/005399 WO2004054569A1 (fr) 2002-12-16 2002-12-16 Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains

Publications (1)

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EP1572191A1 true EP1572191A1 (fr) 2005-09-14

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02781652A Withdrawn EP1572191A1 (fr) 2002-12-16 2002-12-16 Composition pharmaceutique contenant du brevifoliol destinee au traitement chimiotherapeutique d'etres humains

Country Status (2)

Country Link
EP (1) EP1572191A1 (fr)
AU (1) AU2002348815A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004054569A1 *

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AU2002348815A1 (en) 2004-07-09

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