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WO2001058445A1 - Therapie faisant appel a des cannabinoides pour le traitement de tumeurs du cerveau - Google Patents

Therapie faisant appel a des cannabinoides pour le traitement de tumeurs du cerveau Download PDF

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Publication number
WO2001058445A1
WO2001058445A1 PCT/ES2000/000450 ES0000450W WO0158445A1 WO 2001058445 A1 WO2001058445 A1 WO 2001058445A1 ES 0000450 W ES0000450 W ES 0000450W WO 0158445 A1 WO0158445 A1 WO 0158445A1
Authority
WO
WIPO (PCT)
Prior art keywords
cannabinoids
cannabinoid
tumors
malignant
natural
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.)
Ceased
Application number
PCT/ES2000/000450
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English (en)
Spanish (es)
Inventor
Manuel Guzman Pastor
Cristina Sanchez Garcia
Ismael Galve Roperh
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.)
Universidad Complutense de Madrid
Original Assignee
Universidad Complutense de Madrid
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 Universidad Complutense de Madrid filed Critical Universidad Complutense de Madrid
Priority to AU13979/01A priority Critical patent/AU1397901A/en
Priority to DE60020111T priority patent/DE60020111T2/de
Priority to AT00976087T priority patent/ATE295162T1/de
Priority to EP00976087A priority patent/EP1177790B1/fr
Priority to ES00976087T priority patent/ES2241670T3/es
Publication of WO2001058445A1 publication Critical patent/WO2001058445A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention falls within the field of brain tumor therapy.
  • the present invention as set forth in this specification refers to the therapeutic use of cannabinoids for the treatment of brain tumors.
  • the therapies used today for the treatment of these tumors usually be ineffective or at most palliative
  • the invention involves a technically simple approach, lacking noticeable side effects and highly effective for the treatment of brain tumors including the most malignant (glioblastomas)
  • glioblastomas are the most frequent (1 per 50 000 people and year) malignant (mortality close to 100%) and of more rapid evolution (life expectancy of weeks / months after diagnosis )
  • the treatment of glioblastomas is usually ineffective or merely palliative, and involves techniques such as surgery, radiotherapy, chemotherapy and immunotherapy (Louis, DN & Gusella, JF, Trenas Genet.
  • C sativa cannabinoids (Fig 1) carry ac Above its effects because they are similar to certain molecules produced by animals (including humans) that probably play important roles in the nervous system.
  • Cannabinoids both natural and synthetic, act by binding to specific membrane receptors (cannabinoid receptors or CB type), of which two different subtypes CB ⁇ and CB 2 are known today (Pertwee, op cit, Howlett, A er al, in The lUPHAR Compendium of Receptor Characte ⁇ zation and Classification, eds Godframd, T, Humphrey , P Ruffolo, R & Vanhoutte, P, lUPHAR Media, pp 97-104, 1998) Not all The body's tissues possess these receptors are located mainly in the nervous system, and that is why cannabinoids may exert their effects on the brain (Pertwee, op at, Childers, SR & Breivo
  • cannabinoids inhibit the proliferation of MCF-7 breast tumor cells (De Petrocellis, L et al. , Proc Nati Acad. Sci.
  • the present invention makes use of cannabinoids for the treatment of brain tumors for the first time, and is based on our original observations that cannabinoids induce a marked regression (which leads to a lengthening of life) and even eradication (which entails Cure) of ghoblastomas in laboratory animals
  • This invention involves the use of a technically simple therapy, devoid of noticeable side effects and, more importantly, very effective for the treatment of brain tumors, which as mentioned above cannot be treated satisfactorily today with other techniques or compounds
  • the experiments that have led to the present invention are detailed below.
  • C6 glioblastoma cells in the rat brain are widely used as an experimental model of malignant brain tumor (Barth, RF, J Neur ⁇ ncol 36, 91-102, 1998) C6 glioblastoma cells were inoculated directly into the brain of Wistar rats, and tumors were visualized by magnetic resonance imaging All animals that were left untreated died uniformly 12-18 days after cell inoculation (Fig 3a).
  • a group of animals was administered for 7 days THC or WIN-55,212-2 through a cannula located at the site of inoculation.
  • C6 glioblastoma cells were inoculated subcutaneously in mice deficient in RAG-2 recombinase (RAG-2 ' 1 ' ), lacking mature T and B lymphocytes (Shinkai, Y et al, Ce // 68, 855-867 1992)
  • RAG-2 ' 1 ' RAG-2 recombinase
  • Fig 4b the tumor size was extraordinarily smaller in animals treated with THC or WIN-55,212-2 than in control animals
  • Examples of tumor-bearing mice and dissected tumors after treatment with or without cannabinoids for 7 days are shown in Fig 4b
  • cannabinoids did not induce any significant alteration of behavioral parameters such as motor coordination and physical activity. Water and food intake, as well as weight gain, were also not affected by cannabinoids.
  • biochemical parameters glucose and food intake, as well as weight gain, were also not affected by cannabinoids.
  • the biochemical parameters glucose, urea, uric acid, creatinine, cholesterol, bilirubin
  • the markers of tissue damage alanine and aspartate ammotransferases, ⁇ -glutamyltransferase, creatine kinase, lactate dehydrogenase
  • cannabinoids are not only not toxic compounds for nerve cells, but even protect them of toxic stimuli such as glutamatergic agonists (Skaper, SD et al, Pr oc Nati Acad S ⁇ USA 93, 3984-3989, 1996, Shen, M & Thayer,
  • WIN-55,212-2, CP-55,940 and HU-210 induced the death of these cells at doses lower than THC, as expected from its higher affinity for cannabinoid receptors (Pertwee, op at)
  • SR141716 a selective CB antagonist nor SR144528 (a selective CB 2 antagonist)
  • Shire, D et al, Life Sci 65, 627-635, 1999 were able separately to prevent THC-induced cell death.
  • mice have been carried out with glioblastomas as a brain tumor model.
  • the invention can be applied to the treatment of other tumors.
  • brain diseases for example medulloepitheliomas, medulloblastomas, neuroblastomas, germinomas, embryonic carcinomas, astrocytomas, astroblastomas, ependymomas, oligodendrog omas, plexal carcinomas, neuroepitehomas, pineoblastomas, ependyloblastomas, neuroectodermal tumors, malignant melanomas, malignant melanomas
  • the experiments that have led to the present invention have been carried out with two paradigmatic cannabinoids, one natural (THC) and one synthetic (WIN-55,212-2)
  • THC natural
  • WIN-55,212-2 synthetic
  • the cannabinoid with more potent antiproliferative effect will be used for a given
  • C sativa for example ⁇ 8 -tetrah ⁇ drocannab ⁇ nol, cannabinol, cannabidiol
  • Fig 1 synthetic cannabinoids (for example HU-210, CP-55,940, CP-50,556)
  • Fig 2 Pertwee, op ⁇ t, F Barth, op cit)
  • medications that contain any cannabinoid in their composition
  • the experiments that have led to the present invention have been carried out by intratumorally administering the cannabinoid.
  • this will be the chosen route of administration, since it allows a high accessibility of the cannabinoid to the tumor.
  • the route of administration can also be systemic, for example intrape ⁇ toneal, intravenous or oral
  • the experiments that have led to the present invention have been carried out by the continuous administration of a dose of cannabinoid for a certain time.
  • these parameters will be optimized depending on the specific requirements of the treatment patient condition, size and tumor location, number of tumors, etc.
  • the mode of application may be continuous (preferred mode) or sequential in one or more dose per day This will obviously vary the doses of compound administered and the total duration of treatment.
  • Cannabinoid administration to rats began 12 days after cell inoculation.
  • the average tumor size was 70 mm 3 (range 25-100 mm 3 ) estimated by magnetic resonance imaging (Izquierdo et al, op cit, Cortés, by Felipe, Martin Hughes & Izquierdo, op ⁇ t)
  • the cannabinoids were administered by a cannula located at the site of inoculation of the tumor and fixed to the skull with dental cement, a small stainless steel thyme secured the cannula and cement Dental
  • the cannula was connected subcutaneously through a catheter to an osmotic mini-pump (Alzet 2001) that operated at a flow of 1 ⁇ l / h for 7 days
  • the osmotic pump was filled with 500-2500 ⁇ g THC or 50-250 ⁇ g WIN-55,212-2 in 200 ⁇ l of PBS supplemented with 5 mg / ml of ordered and dialyze
  • Fig 3a As seen in Fig 3a, all animals that were left untreated died uniformly 12-18 days after cell inoculation. Animals treated with cannabinoids had a significantly longer life than control animals. Moreover, cannabinoids eradicated completely the tumor in a significant percentage of animals
  • Fig 3b an MRI image of one of the animals cured with THC is shown, after the administration of the cannabinoid the tumor mass disappears completely, and a residual hypointense zone is observed that is interpreted as a fibrous scar at the site of inoculation No recurrence was observed in animals cured with cannabinoids
  • Tumors were induced in RAG-2 ' " mice by subcutaneous inoculation of 5x10 6 cells of C6 ghoblastoma in 100 ⁇ l of PBS supplemented with 0 1% glucose About 10 days later, when the average volume of the tumors was 250 mm 3 (range 200-300 mm 3 ), the animals were randomly divided into 3 groups and injected for 7 days vehicle,
  • the tumor size was extraordinarily smaller in animals treated with THC or WIN-
  • mice bearing tumors and dissected tumors after treatment with or without cannabinoids for 7 days are shown in Fig 4b
  • THC was capable of inducing the death of C6 glioblastoma cells also when added simultaneously SR141716 medium (selective antagonist of CBi) and SR144528 ( a selective antagonist of CB 2) prevented THC-induced cell death
  • Cannabmoids (2500 ⁇ g THC or 250 ⁇ g WIN-55,212-2) were administered to rats without tumors for 7 days as described above. Rats were then sacrificed and their brains fixed. with 4% paraformaldehyde in PBS Death by apoptosis was determined in 40 ⁇ m thick sections of the brain using a "TUNNEL staining kit" according to the supplier's instructions (Boeh ⁇ nger, Mannheim, Germany) DNA stranding with Deoxyundin triphosphate labeled with fluorescein was visualized by a confocal microscope (excitation wavelength 488 nm, length of 525 nm emission wave) The laser intensity and photodetector sensitivity were kept constant to allow comparison between treatments At least 5 optical fields were analyzed per animal
  • TUNNEL stains were performed in the subvent ⁇ cular area of the rat brain, which continues to proliferate in the adult animal.
  • the administration of cannabinoids not only did not produce any significant apoptotic effect on the living brain, but also the slight dizziness observed in the caudate putamen of control animals was not observed in animals treated with cannabinoids

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Radiation-Therapy Devices (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La thérapie faisant appel à des cannabinoïdes pour le traitement de tumeurs du cerveau consiste à administrer (de manière intracrânienne ou systémique) des cannabinoïdes (naturels ou synthétiques) à des mammifères (humains ou non humains) atteints de tumeurs du cerveau. Les cannabinoïdes entraînent, grâce à l'activation de leurs récepteurs spécifiques, la mort sélective des cellules transformées. On assure ainsi la régression ou l'éradication de tumeurs du cerveau sans effets secondaires importants.
PCT/ES2000/000450 2000-02-11 2000-11-22 Therapie faisant appel a des cannabinoides pour le traitement de tumeurs du cerveau Ceased WO2001058445A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU13979/01A AU1397901A (en) 2000-02-11 2000-11-22 Therapy with cannabinoids in the treatment of cerebral tumor
DE60020111T DE60020111T2 (de) 2000-02-11 2000-11-22 Therapeutische anwendung von cannabinoiden zur hirntumorbehandlung
AT00976087T ATE295162T1 (de) 2000-02-11 2000-11-22 Therapeutische anwendung von cannabinoiden zur hirntumorbehandlung
EP00976087A EP1177790B1 (fr) 2000-02-11 2000-11-22 Therapie faisant appel a des cannabinoides pour le traitement de tumeurs du cerveau
ES00976087T ES2241670T3 (es) 2000-02-11 2000-11-22 Terapia con cannabinoides para el tratamiento de tumores cerebrales.

Applications Claiming Priority (2)

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ES200000323U ES1045342Y (es) 2000-02-11 2000-02-11 Expositor giratorio para postales, fotos y similares.
ESP200000323 2000-02-11

Related Child Applications (2)

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US09958960 A-371-Of-International 2001-11-27
US10/647,739 Division US20040039048A1 (en) 2000-02-11 2003-08-25 Therapy with cannabinoid compounds for the treatment of brain tumors

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1307188A4 (fr) * 2000-05-17 2005-07-06 Atlantic Technology Ventures I Medicaments cannabinoides
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
GB2478074A (en) * 2008-06-04 2011-08-24 Gw Pharma Ltd THC and CBD for use in the treatment of tumours
GB2478072A (en) * 2008-06-04 2011-08-24 Gw Pharma Ltd THC and CBD for use in the treatment of brain tumours
US8632825B2 (en) 2008-06-04 2014-01-21 Gw Pharma Limited Anti-tumoural effects of cannabinoid combinations
US8790719B2 (en) 2010-03-12 2014-07-29 Gw Pharma Limited Phytocannabinoids in the treatment of cancer
US9084771B2 (en) 2007-05-17 2015-07-21 Sutter West Bay Hospitals Methods and compositions for treating cancer
US10758514B2 (en) 2013-06-19 2020-09-01 Gw Pharma Limited Use of tetrahydrocannabinol and/or cannabidiol for increasing radiosensitivity in the treatment of a brain tumour
US12121499B2 (en) 2011-09-29 2024-10-22 Gw Pharma Ltd. Pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD)
US12357586B2 (en) 2011-01-04 2025-07-15 Jazz Pharmaceuticals Research Uk Limited Use of the phytocannabinoid cannabidiol (CBD) in combination with a standard anti-epileptic drug (SAED) in the treatment of epilepsy

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BAEK SEUNG-HWA, ET AL.: "Boron trifluoride etherate on silica-A modified Lewis acid reagent (VII). Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells", ARCHIVES OF PHARMACOL. RES., vol. 21, no. 3, June 1998 (1998-06-01), SEOUL, pages 353 - 356, XP000957635 *
BAEK SEUNG-HWA, ET AL.: "Synthesis and antitumor activity of cannabigerol", ARCHIVES OF PHARMACOL. RES., vol. 19, no. 3, 1996, SEOUL, pages 228 - 230, XP000979791 *
BRAUDE M.C. & STEPHEN SZARA: "Pharmacology of marihuana", 1976, RAVEN PRESS, NEW YORK, NY, USA, XP000957683 *
HARRIS L.S. ET AL.: "Retardation of tumor growth by delta-9 tetrahydrocannabinol", THE PHARMACOLOGIST, vol. 16, no. 2, 1974, pages 259, XP000957658 *
RUIZ L. ET AL.: "Delta-9 tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism", FEBS LETT., vol. 458, no. 3, 1999, pages 400 - 404, XP000981226 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1307186A4 (fr) * 2000-05-17 2005-10-19 Atlantic Technology Ventures I Procedes permettant de reduire la proliferation cellulaire fondes sur des acides (3r, 4r)-delta8-tetrahydrocannabinol-11-oiques
EP1307188A4 (fr) * 2000-05-17 2005-07-06 Atlantic Technology Ventures I Medicaments cannabinoides
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US9084771B2 (en) 2007-05-17 2015-07-21 Sutter West Bay Hospitals Methods and compositions for treating cancer
US11344527B2 (en) 2007-05-17 2022-05-31 Sutter Bay Hospitals Methods and compositions for treating cancer
US11260043B2 (en) 2007-05-17 2022-03-01 Sutter Bay Hospitals Methods and compositions for treating cancer
GB2478072A (en) * 2008-06-04 2011-08-24 Gw Pharma Ltd THC and CBD for use in the treatment of brain tumours
US8632825B2 (en) 2008-06-04 2014-01-21 Gw Pharma Limited Anti-tumoural effects of cannabinoid combinations
GB2478074B (en) * 2008-06-04 2012-12-26 Gw Pharma Ltd Anti-tumoural effects of cannabinoid combinations
GB2478072B (en) * 2008-06-04 2012-12-26 Gw Pharma Ltd Anti-tumoural effects of cannabinoid combinations
GB2478074A (en) * 2008-06-04 2011-08-24 Gw Pharma Ltd THC and CBD for use in the treatment of tumours
US8790719B2 (en) 2010-03-12 2014-07-29 Gw Pharma Limited Phytocannabinoids in the treatment of cancer
US9675654B2 (en) 2010-03-12 2017-06-13 Gw Pharma Limited Phytocannabinoids in the treatment of cancer
US12357586B2 (en) 2011-01-04 2025-07-15 Jazz Pharmaceuticals Research Uk Limited Use of the phytocannabinoid cannabidiol (CBD) in combination with a standard anti-epileptic drug (SAED) in the treatment of epilepsy
US12121499B2 (en) 2011-09-29 2024-10-22 Gw Pharma Ltd. Pharmaceutical composition comprising the phytocannabinoids cannabidivarin (CBDV) and cannabidiol (CBD)
US10758514B2 (en) 2013-06-19 2020-09-01 Gw Pharma Limited Use of tetrahydrocannabinol and/or cannabidiol for increasing radiosensitivity in the treatment of a brain tumour

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Publication number Publication date
ES1045342Y (es) 2001-02-16
ES1045342U (es) 2000-08-16

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