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WO1999044600A1 - Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique - Google Patents

Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique Download PDF

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Publication number
WO1999044600A1
WO1999044600A1 PCT/GB1999/000563 GB9900563W WO9944600A1 WO 1999044600 A1 WO1999044600 A1 WO 1999044600A1 GB 9900563 W GB9900563 W GB 9900563W WO 9944600 A1 WO9944600 A1 WO 9944600A1
Authority
WO
WIPO (PCT)
Prior art keywords
fatty acid
oestrogen
tamoxifen
acid
cancer
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/GB1999/000563
Other languages
English (en)
Inventor
David Frederick Horrobin
Richard Bryce
John Hartley
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.)
Scotia Holdings PLC
Original Assignee
Scotia Holdings PLC
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 Scotia Holdings PLC filed Critical Scotia Holdings PLC
Priority to AU26320/99A priority Critical patent/AU2632099A/en
Priority to CA002322856A priority patent/CA2322856A1/fr
Priority to JP2000534202A priority patent/JP2002505279A/ja
Priority to EP99906355A priority patent/EP1058545A1/fr
Publication of WO1999044600A1 publication Critical patent/WO1999044600A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C07C57/12—Straight chain carboxylic acids containing eighteen carbon atoms
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to cancer management. FATTY ACIDS
  • GLA gamma-linolenic acid
  • DGLA dihomogammalinolenic acid
  • EPA eicosapentaenoic acid
  • fatty acids include the essential fatty acids of the n-3 and n-6 series as shown in figure 1 and which include alpha-linolenic acid (ALA, 18:3n- 3), stearidonic acid (SA, 18:4n-3), docosahexaenoic acid (DHA, 22:6n-3), arachidonic acid (AA, 20:4n-6) and adrenic acid (AdrA, 22:4n-6).
  • alpha-linolenic acid ALA, 18:3n- 3
  • SA stearidonic acid
  • DHA docosahexaenoic acid
  • AA arachidonic acid
  • AdrA 22:4n-6
  • Other examples of fatty acids with two or more double bonds which have similar effects include columbinic acid, parinaric acid and conjugated linoleic acid.
  • LA Linoleic acid
  • ALA ⁇ -Linolenic acid
  • GLA Stearidonic acid, (SA) elongation
  • DHA Docosahexaenoic acid
  • the acids which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g .LA as z,z-octadeca - 9,12 - dienoic acid or DHA as z,z,z,z,z,z - docosa- 4,7,10,13,16,19 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient.
  • Initials e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances. 3
  • Another approach to cancer treatment which can improve survival without necessarily leading to substantial tumour shrinkage, is that of hormonal treatment.
  • Some cancers notably of the breast, uterine endometrium and prostate, are frequently dependent on male or female hormones for their growth. More rarely other tumours, including those of the lung, gastrointestinal tract, liver and other organs, may occasionally show some degree of hormone dependency and hence respond to hormone manipulation.
  • Three main types of hormone manipulation are used: removal of the endogenous hormone-secreting organs such as the ovaries, testes, adrenals or pituitary: inhibition of the synthesis of hormones, particularly of oestrogens or androgens; and antagonism of the actions of hormones by blocking binding to their receptors.
  • Drugs which inhibit hormone synthesis include gonadotrophin-releasing hormone (GnRH) and synthetic analogues of the hormone which interact with the GnRH receptor: these block the controlling drive to the ovaries and testes. They also include inhibitors of steroid hormone synthesis such as aromatase inhibitors (e.g. aminoglutethimide, 4-hydroxyandrostenedione, plomestane, exemastane, pyridoglutethimide, fadrazole, vorazole, arimidex, CGS20267 and other drugs in development) and other steroid synthesis inhibitors which may work by various mechanisms, including cytochrome P450-dependent steroidogenesis (e.g. ketoconazole, miconazole and CGS16949A). The overall effect of these synthesis-inhibiting hormones is to reduce the production of steroids by the ovaries, testes or adrenals.
  • GnRH gonadotrophin-releasing hormone
  • steroids e.g. aminogluteth
  • anti-oestrogens are in development, including 4- hydroxytamoxifen, toremifene, ICI- 164384 and ICI-182780.
  • anti-androgens including cyproterone acetate, flutamide, nilutamide and
  • ICI- 176334 Another mechanism of anti-androgen action is to block the conversion of testosterone to dihydrotestosterone, which is the final active androgen in the prostate. This reaction is catalysed by the enzyme 5-alpha- reductase and can be blocked by finasteride and a range of similar drugs. All hormone therapies seem to have approximately similar results in terms of response rates and there do not appear to be major differences between them (RC Stein et al, pp 629-648, in the Oxford Textbook of Oncology, Volume 1, Oxford University Press, 1995).
  • the World Health Organisation has defined responses as follows: complete response (CR) is disappearance of all signs and symptoms of the cancer; partial response (PR) is decreasing by more than 50% of the sum of the two largest perpendicular diameters of measurable lesions; stable disease (SD) is no significant change (less than 50% shrinkage or 25% growth) of the tumour; progressive disease (PD) is growth of more than 25% in size of the tumour or the appearance of new lesions.
  • complete response is disappearance of all signs and symptoms of the cancer
  • partial response is decreasing by more than 50% of the sum of the two largest perpendicular diameters of measurable lesions
  • stable disease (SD) is no significant change (less than 50% shrinkage or 25% growth) of the tumour
  • progressive disease (PD) is growth of more than 25% in size of the tumour or the appearance of new lesions.
  • the patent literature includes Neuromedica WO 97/44026 and Biosignal WO 94/12530.
  • Neuromedica concerns taxol and analogues interfering with cell division, particularly taxotere, and to combat non-solubility and non-specificity to cancer cells proposes taxotere/fatty acid conjugates, optionally used with other anticancer drugs including tamoxifen in the form of tamoxifen methionine or tamoxifen citrate.
  • the fatty acid is present to help, for example, in the crossing of the blood brain barrier by the drug.
  • Biosignal propose quite different compounds, fatty-acyl derivatives of peptides, for example DHA or EPA conjugates of a somatostatin analogue or a gonadotrophin releasing hormone.
  • the invention is as set out in the claims but in one aspect lies in the use in effective amounts, in the preparation of a medicament for the management of cancer, of tamoxifen or other anti-oestrogen together with an unsaturated fatty acid containing two or more cis or trans double bonds, the fatty acid being as such or as a bio-available derivative as discussed below.
  • Such derivatives are present to deliver the fatty acid, and do not include derivatives of drugs, unless the anti-oestrogen itself forms such a derivative.
  • Anti-oestrogens such as tamoxifen or toremifene that are basic may be presented as salts with the fatty acids, and such salts are new and an aspect of the invention.
  • esters with the fatty acids may be presented as esters with the fatty acids. These esters may be formed directly with the fatty acid or for example with the fatty acid and the drug linked through a hydroxy/-carboxyl linker compound such as 1,3- 10
  • the invention extends further to medicaments as such, containing the fatty acid and anti-oestrogen as such or as derivatives particularly the new salts or derivatives above, and to therapy lying in the cancer management itself. Management is not only in particular in respect of the reduction of tumour size, as shown in the study reported above, but also in prophylaxis. The synergy is to be expected in preventive mode as much as in overt disease as this is essentially early treatment of cancerous or pre-cancerous cells before any development of tumours has taken place.
  • tamoxifen with GLA or DGLA Especially use is made of tamoxifen with GLA or DGLA, and especially the cancer is breast cancer.
  • the fatty acid suitably C 1 to C 26 , may in particular be an n-6 or n-3 essential fatty past the delta-6 desaturation step, particularly GLA, DGLA, SA, EPA or DHA, or it may be columbinic acid, parinaric acid or conjugated
  • the medicament is in single or divided dosage form suited to administration of daily amounts of the anti- oestrogen conventional for its use 11
  • the fatty acids may be provided orally or parenterally in any bio- available form including the free acid, salts such as lithium, sodium, potassium, zinc or any other salt; mono-, di- or triglycerides; ethyl or other esters suitably Ci to C 6 alkyl; cholesterol esters; phospholipids; amides suitably Ci to C 6 alkyl; or any other pharmacologically acceptable derivatives delivering the acid in the required amount including the diol derivatives of the applicant's PCT WO 96/34846 and PCT WO 96/34855.
  • Such derivatives are of materials not acting as drugs in themselves, unless possibly of the anti-oestrogen forming the other component of the composition, where so derivatisable.
  • Bioavailability may for example be shown by the derivatives giving the effects of the fatty acids or their natural glyceride esters, or by direct analysis of fatty acid concentrations in blood plasma or other tissues by standard techniques for example those of Pelick et al p.23 "Analysis of Lipids and Lipoproteins” Ed. Perkins, Am. Oil Chemists Soc, Champaign, Illinois, USA.
  • a stock solution of eicosa-4Z,7Z,10Z,13Z,16Z-pentaenoic acid (195mg. 0.65mmol)in dichloromethane (2.5mL) was prepared.
  • a second stock solution of 1,3-dicyclohexylcarbodiimide (150mg, 0.72mmol) and 4-(N,N- dimethylamino)pyridine (90mg, 0.72mmol) in dichloromethane (2.5mL) was also prepared.
  • An aliquot (0.25mL) of each of these solutions was added to 4- hydroxytamoxifen (25mg. 0.065mmol) and the mixture was gently shaken until a clear solution resulted.
  • the anti-oestrogen is a 60mg tablet of toremifene instead of the tamoxifen or other conventional amount of 30 to 240 mg daily.
  • the fatty acid is one of DGLA, SA, EPA, DHA, or other n-6 or n-3 essential fatty acid past the delta-6 desaturation step, or columbinic acid, parinaric acid or conjugated linoleic acid, instead of GLA, in corresponding molar amount.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'association du tamoxifène et de l'acide gammalinolénique produit une forte action synergique utilisée pour le traitement du cancer et la préparation de médicaments anticancéreux.
PCT/GB1999/000563 1998-03-02 1999-02-24 Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique Ceased WO1999044600A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU26320/99A AU2632099A (en) 1998-03-02 1999-02-24 Cancer management with tamoxifen and gammalinolenic acid
CA002322856A CA2322856A1 (fr) 1998-03-02 1999-02-24 Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique
JP2000534202A JP2002505279A (ja) 1998-03-02 1999-02-24 癌管理
EP99906355A EP1058545A1 (fr) 1998-03-02 1999-02-24 Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9804361.5 1998-03-02
GBGB9804361.5A GB9804361D0 (en) 1998-03-02 1998-03-02 Cancer treatment

Publications (1)

Publication Number Publication Date
WO1999044600A1 true WO1999044600A1 (fr) 1999-09-10

Family

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Family Applications (1)

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PCT/GB1999/000563 Ceased WO1999044600A1 (fr) 1998-03-02 1999-02-24 Traitement du cancer a l'aide de tamoxifene et d'acide gammalinolenique

Country Status (7)

Country Link
EP (1) EP1058545A1 (fr)
JP (1) JP2002505279A (fr)
AU (1) AU2632099A (fr)
CA (1) CA2322856A1 (fr)
GB (1) GB9804361D0 (fr)
WO (1) WO1999044600A1 (fr)
ZA (1) ZA991619B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
WO2012141575A1 (fr) * 2011-04-14 2012-10-18 N.V.Nutricia Combinaison d'epa, de dpa et/ou de dha avec un agent chimiothérapeutique
US10639313B2 (en) 2017-09-01 2020-05-05 Ndsu Research Foundation Compound for inhibition of delta-5-desaturase (D5D) and treatment of cancer and inflammation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4382735B2 (ja) 2005-10-06 2009-12-16 独立行政法人科学技術振興機構 神経因性疼痛治療剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012530A1 (fr) * 1992-11-30 1994-06-09 Biosignal Kutató Fejlesztó Kft. Composition d'un peptide et d'un acyle gras polyinsature
EP0707850A1 (fr) * 1994-09-21 1996-04-24 Scotia Holdings Plc Utilisation d'acides gras polyinsaturés pour la fabrication d'un médicament pour le traitement des douleurs des seins
WO1996034855A1 (fr) * 1995-05-01 1996-11-07 Scotia Holdings Plc Esters d'acides gras utilises comme composes bioactifs
WO1997044026A1 (fr) * 1996-05-22 1997-11-27 Neuromedica, Inc. Compositions contenant des conjugues d'acide cis-docosahexanoique et de taxotere

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012530A1 (fr) * 1992-11-30 1994-06-09 Biosignal Kutató Fejlesztó Kft. Composition d'un peptide et d'un acyle gras polyinsature
EP0707850A1 (fr) * 1994-09-21 1996-04-24 Scotia Holdings Plc Utilisation d'acides gras polyinsaturés pour la fabrication d'un médicament pour le traitement des douleurs des seins
WO1996034855A1 (fr) * 1995-05-01 1996-11-07 Scotia Holdings Plc Esters d'acides gras utilises comme composes bioactifs
WO1997044026A1 (fr) * 1996-05-22 1997-11-27 Neuromedica, Inc. Compositions contenant des conjugues d'acide cis-docosahexanoique et de taxotere

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL PHARMACOLOGY, (1994 JUN 1) 47 (11) 1989-98. *
BRITISH JOURNAL OF CANCER, (1998) VOL. 78, NO. SUPPL. 2, PP. 45. MEETING INFO.: JOINT MEETING OF THE BRITISH ONCOLOGICAL ASSOCIATION, THE ASSOCIATION OF CANCER PHYSICIANS AND THE ROYAL COLLEGE OF RADIOLOGISTS NOTTINGHAM, ENGLAND, UK JULY 5-7, 1998 AS *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; DE ANTUENO, R. ET AL: "Effect of polyunsaturated fatty acid propane diol esters on mice treated with tamoxifen.", XP002108764, retrieved from STN *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; KENNY, F. S. (1) ET AL: "Gamma linolenic acid with tamoxifen as primary therapy in breast cancer.", XP002108763, retrieved from STN *
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; LOCKWOOD K. ET AL: "Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.", XP002108766, retrieved from STN Database accession no. 95041313 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; BORRAS M ET AL: "Modulatory effect of nonesterified fatty acids on structure and binding characteristics of estrogen receptor from MCF-7 human breast cancer cells.", XP002108767, retrieved from STN Database accession no. 93095048 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; CUSTODIO J B ET AL: "Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity.", XP002108765, retrieved from STN Database accession no. 94280430 *
HORROBIN D F: "NUTRITIONAL AND MEDICAL IMPORTANCE OF GAMMA-LINOLENIC ACID", PROGRESS IN LIPID RESEARCH, vol. 31, no. 2, 1 January 1992 (1992-01-01), pages 163 - 194, XP000196482, ISSN: 0163-7827 *
JOURNAL OF RECEPTOR RESEARCH, (1992) 12 (4) 463-84. *
MOLECULAR ASPECTS OF MEDICINE, (1994) 15/SUPPL. (S231-S240). *
PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING, (MARCH, 1999) VOL. 40, PP. 361. MEETING INFO.: 90TH ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH PHILADELPHIA, PENNSYLVANIA, USA APRIL 10-14, 1999 AMERICAN *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
WO2012141575A1 (fr) * 2011-04-14 2012-10-18 N.V.Nutricia Combinaison d'epa, de dpa et/ou de dha avec un agent chimiothérapeutique
WO2012141590A1 (fr) * 2011-04-14 2012-10-18 N.V. Nutricia Combinaison d'epa, de dpa et/ou de dha avec un agent chimiothérapeutique
US10639313B2 (en) 2017-09-01 2020-05-05 Ndsu Research Foundation Compound for inhibition of delta-5-desaturase (D5D) and treatment of cancer and inflammation

Also Published As

Publication number Publication date
AU2632099A (en) 1999-09-20
JP2002505279A (ja) 2002-02-19
ZA991619B (en) 2000-01-20
EP1058545A1 (fr) 2000-12-13
GB9804361D0 (en) 1998-04-22
CA2322856A1 (fr) 1999-09-10

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