EP1119353A1 - Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine - Google Patents

Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine

Info

Publication number
EP1119353A1
EP1119353A1 EP99950209A EP99950209A EP1119353A1 EP 1119353 A1 EP1119353 A1 EP 1119353A1 EP 99950209 A EP99950209 A EP 99950209A EP 99950209 A EP99950209 A EP 99950209A EP 1119353 A1 EP1119353 A1 EP 1119353A1
Authority
EP
European Patent Office
Prior art keywords
limocitrin
administering
carcinoma
effective amount
composition
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Withdrawn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
EP99950209A
Other languages
German (de)
English (en)
Other versions
EP1119353A4 (fr
Inventor
Najla Guthrie
John A. Manthey
Robert M. Horowitz
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.)
KGK Synergize Inc
US Department of Agriculture USDA
Original Assignee
KGK Synergize Inc
US Department of Agriculture USDA
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 KGK Synergize Inc, US Department of Agriculture USDA filed Critical KGK Synergize Inc
Publication of EP1119353A1 publication Critical patent/EP1119353A1/fr
Publication of EP1119353A4 publication Critical patent/EP1119353A4/fr
Withdrawn legal-status Critical Current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
    • A61K31/33—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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to compositions and methods for the prevention
  • the present invention also relates to compositions and methods for the prevention and treatment of atherosclerosis, thrombosis, inflammatory diseases, allergies or viral diseases. These compounds are a group of naturally occurring
  • limocitrin-derived compounds 3,5,7,4'-tetramethoxylimocitrin, 3,7,4'-trimethoxylimocitrin,
  • Limocitrin analogues are a group of citrus-derived flavonoids that are naturally
  • 5-desmethoxy sinensetin is chemically
  • Flavonoids are polyphenolic compounds that
  • flavonoids occur ubiquitously in foods of plant origin.
  • the major dietary sources of flavonoids are
  • Plants have evolved flavonoids as protection against parasites, herbivores, and
  • flavonoids contribute to the color of fruits
  • dietary flavonoids in the United States has been estimated at lg/day expressed as glycosides, of which about 170 mg expressed as aglycones, consist of flavonols, flavonones and flavones (Kuhnau, J., 1976, World Rev. Nutr. Diet 24:fl 17-191). Flavonol and flavone intake thus exceeds that of other dietary antioxidants such as beta-carotene (2-3mg/day) and vitamin E (7-10mg/day) and equals approximately one-third of vitamin C (70-100mg/day) (Nutrient intakes. Individuals in 48 states. Year 1977-1978. Report No. 1-2. Consumer Nutrition
  • Flavonoids have been demonstrated to be the most potent dietary antioxidants and in light of
  • flavonoids make a major contribution to the antioxidant
  • the main food sources of flavonols and flavones are black tea,
  • Flavonol and flavone intake was inversely associated with mortality from coronary heart disease and to a lesser
  • Flavonol and flavone intake (mainly quercetin) was also inversely associated with stroke risk (Hertog,
  • antithrombotic, anticoronary heart disease, antimyocardial infarction and/or antistroke agents are examples of antithrombotic, anticoronary heart disease, antimyocardial infarction and/or antistroke agents.
  • Chemotherapeutic agents share one characteristic: they are usually more effective in killing or damaging malignant cells than normal cells. However, the fact that they do harm normal cells indicates their potential toxicity. Animal tumor investigations and human clinical trials have shown that drug combinations produce higher rates of objective response and longer survival than
  • Combination drug therapy is, therefore, the basis for most chemotherapy employed at present (DeVita, V.T. et al., 1995, Cancer 35:98).
  • Cancer treatment requires inhibition of a variety of factors including tumor cell
  • neoplastic cells especially in disease states such as breast cancer.
  • the present invention is directed to a method for the prevention and/or
  • the present invention is also directed to a method for the prevention and/or
  • the present invention is also directed to a method for the prevention and/or treatment of atherosclerosis, myocardial infarction, stroke or thrombosis, which involves
  • the present invention is further directed to a method for inducing anti-
  • the present invention is directed to the use of limocitrin analogues and 5-
  • the present invention is directed to a method for the prevention and/or
  • the present invention is also directed to a method for inhibiting the oxidation of low-density lipoproteins and platelet aggregation and adhesion, which involves using an
  • the present invention is also directed to a method of administering an
  • the method of the invention involves administering an effective dose of a one or a combination of limocitrin analogues and 5-desmethyl sinensetin, tamoxifen or a chemotherapeutic agent, in an individual who is identified as being at enhanced risk for
  • cancer and/or as having cancer, in order to prevent and/or treat cancer.
  • the method of the invention also involves administering an effective dose of limocitrin analogues and 5-desmethyl sinensetin to an individual who is identified as being at
  • myocardial infarction or thrombosis in order to prevent and treat coronary heart diseases.
  • Cancer can be viewed as a
  • a cell acquires the ability to "override' these signals and to proliferate under conditions in which normal cells would not grow.
  • the tumor must acquire vasculature to
  • a threefold to fourfold increase in risk for breast cancer include (1) first-degree female family
  • chemo-therapeutic agent has not been reported for the prevention and treatment of neoplastic
  • nutraceuticals or considered as foods or parts of foods but which provide health benefits.
  • the methoxylated flavones are anticipated to have very low cytotoxicity,
  • flavones show very low toxicity compared with polyhydroxylated flavones.
  • methoxylated and ethoxylated limocitrin analogues and 5-desmethyl sinensetin of the present invention will also have this important advantage over other dietary anti-cancer flavonoids.
  • the present invention provides a number of different limocitrin compounds
  • the present invention further provides the structurally-related compound, 5-desmethyl
  • sarcomas and carcinomas include, but are not limited to, human sarcomas and carcinomas, e.g. carcinomas, e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
  • carcinomas e.g., colon carcinoma
  • pancreatic cancer breast cancer, ovarian cancer, prostate cancer
  • fibrosarcoma myxosarcoma
  • liposarcoma liposarcoma
  • osteogenic sarcoma chondroma
  • angiosarcoma endo
  • rhabdomyosarcoma squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat
  • gland carcinoma sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal
  • carcinoma Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung
  • carcinoma bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
  • craniopharyngioma ependymoma, pinealoma, hemangioblastoma, acoustic neuroma
  • oligodendroglioma meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g.,
  • acute lymphocytic leukemia and acute myelocytic leukemia myeloblastic, promyelocytic,
  • myelomonocytic, monocytic and erythroleukemia myelomonocytic, monocytic and erythroleukemia
  • chronic leukemia chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia
  • polycythemia vera myelomonocytic, monocytic and erythroleukemia
  • chronic leukemia chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia
  • polycythemia vera polycythemia vera
  • lymphoma Hodgkin's disease and non-Hodgkin's disease
  • multiple myeloma Waldenstrom's
  • macroglobulinemia and heavy chain disease. Specific examples of such cancers are described in the sections below.
  • age elevated plasma cholesterol level, high arterial blood pressure, cigarette smoking, reduced high-density lipoprotein (HDL) cholesterol level, or family history of premature coronary artery disease.
  • HDL high-density lipoprotein
  • Elevation of HDL or alpha fraction has a negative correlation with
  • HDL exerts a protective
  • LDL cholesterol levels should have a measurement of LDL. LDL cholesterol levels are then classified as borderline-
  • LDL levels greater than 189 mg/dl and for those patients with LDL cholesterol levels between 159 and 189 mg/dl who have two or more additional risk factors.
  • drugs that have been used to reduce serum cholesterol levels are cholestyramine, colestipol, clofibrate, gemfibrozil and lovastatin.
  • Flavonoids inhibit platelet aggregation and adhesion ( Frankel, E.N. et al., 1993,
  • Flavonoids antagonize thromboxane formation and increase platelet
  • the medical therapy includes, but is not limited
  • beta-adrenergic blocking agents e.g., propranonol, nadolol, timolol, etc.
  • nitrates e.g., nitroglycerin
  • calcium channel blockers e.g., calcium channel blockers
  • Limocitrin occurs in the
  • peel of lemon as limocitrin-3-0-glucoside and can be produced from the 3-glucoside by
  • the present invention provides a number of different analogues of limocitrin
  • Flavonoids share the common skeleton of diphenylpyrans, e.g., two benzene
  • Compounds structurally related to limocitrin and 5-desmethyl sinensetin may be formulated into pharmaceutical preparations for administration to humans for prevention and treatment of neoplastic diseases and/ or cardiovascular disease, atherosclerosis,
  • the therapeutic compounds or pharmaceutical compositions may be administered intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally,
  • Formulations suitable for oral administration include liquid solutions of the
  • active compound dissolved in diluents such as saline, water or PEG 400; capsules or tablets,
  • Formulations suitable for parenteral administration include aqueous and non-
  • aqueous isotonic sterile solutions which contain buffers, antioxidants and preservatives.
  • the formulations may be in unit dose or multi-dose sealed containers.
  • Patient dosages for oral administration of limocitrins range from 1-1000 mg/day. commonly 1-500 mg/day, and typically from 1-100 mg/day. Stated in terms of
  • Dosage amount and interval may be adjusted individually to provide plasma
  • a variety of delivery systems for the pharmacological compounds may be
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • Such carriers or excipients include, but are not limited to, calcium carbonate, calcium
  • phosphate various sugars, starches, cellulose derivatives, gelatin, and polymers such as
  • liposomes for example, in a liposome coated with tumor-specific antibody.
  • the liposomes will be targeted to and taken up selectively by the tumor.
  • concentration of the drug may not be related to plasma concentration.
  • Thymidine was purchased from ICN, Irvine, CA.
  • MDA-MB-435 estrogen receptor-negative human breast cancer cells were maintained at 37°C in a minimum essential medium, supplemented with 10% (v/v) fetal bovine serum. The medium was equilibrated with a humidified atmosphere of 5% CO 2 . Stock cultures were seeded at a density of 2 x 10 4 cells/ml and allowed to multiply for 48 to 72 hours.
  • MCF-7 estrogen receptor-positive human breast cancer cells were routinely maintained in minimum essential medium supplemented with 10% (v/v) fetal calf serum, 1 mM sodium pyruvate, lO ⁇ g/ml bovine insulin and 1% (v/v) antibiotic-antimycotic agents (10,000 units/ml penicillin G sodium, 10,000 ⁇ g/ml streptomycin sulfate and 25 ⁇ g/ml amphtericin B in 0.85% saline). Cells were grown to confluence at 37°C in a humidified atmosphere containing 5% CO in air and were passaged weekly, using 2% trypsin in citrate saline.
  • MDA-MB-435 cells were plated at 2 x 10 4 cells/well in 96-well, flat bottomed
  • the cells were harvested onto a glass fiber filter paper using a semiautomatic 12-well cell
  • the MCF-7 cells were seeded at a density of 2 x 10 4 cells/well in 96- well, flat bottomed tissue culture plates and were incubated at 37°C for 5 days.
  • Viability of cells was measured by MTT assay (Hansen, M.B. et al., J. Imm.
  • MDA-MB-435 cells (8xl0 4 /well) were seeded with
  • Results are the average of 3 experiments.
  • the two synthetic analogues, limocitrin 3,5,7,4'-tetraethyl ether and limocitrin 3,7,4'-trimethyl ether 5-acetate were the two synthetic analogues, limocitrin 3,5,7,4'-tetraethyl ether and limocitrin 3,7,4'-trimethyl ether 5-acetate.
  • trimethoxylimocitrin was the least effective having an IC 50 of 3.1 ppm in ER- cells and 0.5 in
  • ER+ cells (Table 1). Tamoxifen, a drug widely used for the treatment of ER+ tumors has an
  • limocitrin compounds are potent inhibitors of both ER- and ER+ cells and are less likely to

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions et des procédés de prévention et de traitement de maladies néoplastiques et de l'athérosclérose. Des individus très susceptibles de développer une maladie néoplastique ou l'athérosclérose ou déjà atteints de ces maladies et soumis à un traitement classique peuvent être traités avec une dose effective de composés à base de limocitrine, y compris, entre autres, 3,5,7,4'-tétraméthoxylimocitrine, 3,5,7,4'-triméthyl-éther-5-acétate de limocitrine, 3,5,7,4'-tétraméthoxylimocitrine ou 3,7,4'-triméthoxylimocitrine, et 5-desméthyl-sinensétine.
EP99950209A 1998-10-06 1999-10-05 Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine Withdrawn EP1119353A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16763498A 1998-10-06 1998-10-06
US167634 1998-10-06
PCT/US1999/023238 WO2000019998A1 (fr) 1998-10-06 1999-10-05 Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine

Publications (2)

Publication Number Publication Date
EP1119353A1 true EP1119353A1 (fr) 2001-08-01
EP1119353A4 EP1119353A4 (fr) 2002-08-28

Family

ID=22608155

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99950209A Withdrawn EP1119353A4 (fr) 1998-10-06 1999-10-05 Compositions et procedes pouvant inhiber des maladies neoplastiques au moyen de composes apparentes a limocitrine et 5-desmethyl-sinensetine

Country Status (5)

Country Link
EP (1) EP1119353A4 (fr)
JP (2) JP2003509334A (fr)
AU (1) AU6291699A (fr)
CA (1) CA2346333A1 (fr)
WO (1) WO2000019998A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6413533B1 (en) * 1998-05-07 2002-07-02 The University Of Tennessee Research Corporation Method for chemoprevention of prostate cancer
US6987125B1 (en) 1998-10-06 2006-01-17 The United States Of America As Represented By The Secretary Of Agriculture Compositions and methods of treating, reducing and preventing cardiovascular diseases and disorders with polymethoxyflavones
US20060135445A1 (en) * 2003-02-04 2006-06-22 Kabushiki Kaisha Yakult Honsha Breast cancer-resistant protein inhibitor
JP2008513350A (ja) * 2005-05-24 2008-05-01 ケージーケー シナジャイズ インコーポレイテッド フラボノイドとトコトリエノールを含む組成物及びその方法
WO2008035208A2 (fr) * 2006-05-19 2008-03-27 Kgk Synergize Inc Utilisation de flavonoïdes pour inhiber la croissance cellulaire
CN102731459B (zh) * 2012-06-15 2014-05-28 南京中医药大学 灯盏乙素苷元Mannich衍生物及其制备方法和应用
US9132117B2 (en) 2013-06-17 2015-09-15 Kgk Synergize, Inc Compositions and methods for glycemic control of subjects with impaired fasting glucose
KR20230161639A (ko) * 2022-05-19 2023-11-28 제주대학교 산학협력단 제주쑥 추출물을 함유하는 항암용 조성물
CN115813991A (zh) * 2022-11-29 2023-03-21 三峡大学 一种柑橘属果实提取物在制备治疗乳腺癌内分泌药物中的应用

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US3867541A (en) * 1972-05-03 1975-02-18 Ralph C Robbins Compositions and methods for disaggregating blood cells
US3903266A (en) * 1972-05-03 1975-09-02 Ralph C Robbins Compositions and methods for disaggregating blood cells
JPH0617304B2 (ja) * 1982-09-09 1994-03-09 理化学研究所 制癌剤
JPH06116164A (ja) * 1992-10-07 1994-04-26 Otsuka Pharmaceut Co Ltd 癌の併用化学療法剤
ZA941290B (en) * 1993-02-26 1995-08-25 Res Dev Foundation Combination cisplatin/tamoxifen therapy for human cancers
US5336685A (en) * 1993-04-12 1994-08-09 Sloan-Kettering Institute For Cancer Research Use of flavonoids to treat multidrug resistant cancer cells
JPH08310952A (ja) * 1995-03-16 1996-11-26 Takeda Chem Ind Ltd 医薬組成物
JP2000500138A (ja) * 1995-11-07 2000-01-11 イーライ・リリー・アンド・カンパニー 耐性腫瘍の治療方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUTHRIE N ET AL: "INHIBITION OF MAMMARY CANCER BY CITRUS FLAVONOIDS" ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, SPRING ST., NY, US, vol. 439, 1998, pages 227-236, XP000995351 ISSN: 0065-2598 *
See also references of WO0019998A1 *

Also Published As

Publication number Publication date
EP1119353A4 (fr) 2002-08-28
WO2000019998A1 (fr) 2000-04-13
CA2346333A1 (fr) 2000-04-13
JP2005015469A (ja) 2005-01-20
JP2003509334A (ja) 2003-03-11
AU6291699A (en) 2000-04-26

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