WO2002089919A2 - Utilisation du zinc dans la prevention d'une pathologie induite par tnf pendant une therapie contre le cancer - Google Patents

Utilisation du zinc dans la prevention d'une pathologie induite par tnf pendant une therapie contre le cancer Download PDF

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Publication number
WO2002089919A2
WO2002089919A2 PCT/EP2002/005222 EP0205222W WO02089919A2 WO 2002089919 A2 WO2002089919 A2 WO 2002089919A2 EP 0205222 W EP0205222 W EP 0205222W WO 02089919 A2 WO02089919 A2 WO 02089919A2
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WO
WIPO (PCT)
Prior art keywords
tnf
zinc
mice
znso
induced
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PCT/EP2002/005222
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English (en)
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WO2002089919A3 (fr
Inventor
Tino Hochepied
Claude Libert
Wim Van Molle
Ben Wielockx
Original Assignee
Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw
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.)
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Publication date
Application filed by Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw filed Critical Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw
Publication of WO2002089919A2 publication Critical patent/WO2002089919A2/fr
Publication of WO2002089919A3 publication Critical patent/WO2002089919A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • 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 is based on the finding that treatment with the heavy metal zinc, in combination with tumour necrosis factor (TNF) and/or interferon-gamma (IFN- ⁇ ), results in significant tumour destruction and complete protection against TNF-induced lethal-shock.
  • TNF tumour necrosis factor
  • IFN- ⁇ interferon-gamma
  • TNF is generally considered to be the major mediator of both the shock-inducing and anti-tumour activities of Gram-negative LPS (1). Indeed, especially in combination with IFN- ⁇ , TNF holds much promise for anti-tumour therapy, provided its systemic toxicity can be suppressed. Therefore, reduction of the systemic lethal inflammatory shock induced by TNF could lead to a breakthrough both for the use of TNF in treatment of cancer patients and for the inhibition of cardiovascular shock and other diseases in which TNF is involved.
  • endogenous protective mechanisms against TNF- induced shock exist: for example, mice can be de-sensitized using a single dose of IL- 1 (2) or tolerized by repetitive administration of sub-lethal amounts of TNF (3).
  • TNF is a potent antitumor drug but that its application is seriously hampered by its toxicity.
  • the present invention discloses that the heavy metal zinc confers complete protection against TNF-induced lethality, hypothermia, induction of IL-6 and bowel necrosis by simple addition in the drinking water.
  • the present invention also demonstrates that zinc, surprisingly, does not inhibit the anti-tumour activities of TNF/IFN- ⁇ and leads to a significantly better survival after a TNF/IFN- ⁇ combination therapy. Therefore, the present invention aims at providing a superior method to prevent or treat cancer therapy-induced pathology.
  • the present invention aims at providing a molecule that blocks the systemic toxicity induced or modulated by TNF but, at the same time, does not affect the cytotoxic, anti- tumour activity of TNF. Furthermore, the present invention aims at providing the usage of zinc, preferably a zinc salt, to, in addition to TNF and/or IFN- ⁇ , treat cancer or other disease states in which the cytotoxic/anti-tumour activity of TNF is preferred but in which the systemic toxicity of TNF has to be partially or completely blocked. The present invention further aims at providing a method wherein the usage of zinc precedes the usage of TNF and/or IFN- ⁇ to prevent or treat the latter diseases.
  • the present invention also aims at providing a pharmaceutical composition comprising zinc or a salt thereof such as ZnSO 4 for use as a medicament to prevent or treat cancer or other disease states in which the cytotoxic/anti-tumour activity of TNF is preferred but in which the systemic toxicity of TNF has to be partially or completely blocked.
  • Panel A shows the tumor size index over a period of 20 days
  • panel B shows % survival of mice over a period of 20 days.
  • the present invention is based on the surprising finding that simple treatment in the drinking water with the heavy metal zinc, in addition to tumour necrosis factor (TNF) and interferon-gamma (IFN- ⁇ ), results in significant tumour destruction and complete protection against TNF-induced lethal-shock.
  • TNF tumour necrosis factor
  • IFN- ⁇ interferon-gamma
  • the present invention thus relates to the usage of zinc to prevent and/or treat pathology, and more specifically to prevent or treat any TNF-induced pathology.
  • the term 'pathology' refers to any cause and effect of disease.
  • the 'systemic toxicity of TNF' or 'TNF-induced pathology' is a well-known biological activity of TNF (1). More specifically, the term 'TNF-induced pathology' relates to TNF- induced lethality, hypothermia, induction of IL-6 and bowel necrosis. Also the 'tumour- killing', 'tumoricidaP or cytotoxic' activity of TNF is well described (1).
  • the term 'TNF' relates in first instance to TNF-alpha, preferentially human TNF-alpha (Vassalli, 1992), but also includes TNF-beta or lymphotoxin.
  • 'zinc' refers to soluble Zn 2+ and water-soluble zinc salts such as ZnSO 4 , ZnCI 2 , ZnO, zinc-bis-(DL-hydrogenaspartate), zinc acetate, zinc carbonate, zinc alpha D glucoheptonate, zinc nitrate, zinc perchlorate and zinc sulfide
  • the term 'medicament to prevent and/or treat' relates to a composition comprising zinc as described above and, if needed, a pharmaceutically acceptable carrier or excipient (both terms can be used interchangeably) to prevent and/or treat diseases as indicated above.
  • compositions comprising zinc, or a pharmaceutically acceptable salt thereof may be by way of oral, parenteral such as intravenal or intraperitoneal or rectal administration.
  • the active compound (zinc) may be administered alone or together with any other active or non-active substance preferably formulated as a pharmaceutical composition.
  • An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 10 mg or 0.01 to 50 g (for example 0.01 to 10 g, or 0.05 to 2 g) of zinc or a pharmaceutically acceptable salt thereof.
  • Unit doses will normally be administered once or more than once a day, for example 1, 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is in the range of 0.0003 to 3 g per kg per day; thus a suitable total daily dose for a 70 kg adult is 0.4 to 200 g, for example 0.4 to 150 g or more usually 2 to 150 g. It is greatly preferred that the compound or a pharmaceutically acceptable salt thereof is administered in the form of a unit-dose composition, such as a unit dose oral, or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories or aerosols.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • compositions for inhalation are presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns, for example between 1 and 5 microns, such as between 2 and 5 microns.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the active compound can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • mice C57BL/6 mice were purchased from Iffa-Credo (Saint Germain-sur-l'Arbresle, France) and were used at the age of 8-12 weeks. Mice were kept in a conventional air- conditioned mouse room in 12-h light/dark cycles, and received food and water ad libitum. Experimental procedures. ZnSO 4 , purchased from Sigma Chemical Co. (St. Louis, MO), was dissolved in distilled water at a concentration of 25 mM. Mice were treated with ZnSO 4 or distilled water for 7 days. The B16BL6 melanoma subline, selected from a spontanous melanoma B16F10 line by I.
  • the tumor size index (TSI) was obtained with the following formula: largest diameter of the tumor x perpendicular diameter x 0.4.
  • IL-6 was determined as described previously (6). IL-6-dependent 7TD1 cells were cultured in 96-well microtiter plates (7000 cells/well) in the presence of medium, serial dilutions of serum, or a murine IL-6 standard. After 3 days of culture, the number of living cells was determined in a hexosaminidase colorimetric assay; titers were assigned by comparing the dilutions of samples and standard needed to obtain half-maximal growth of 7TD1 cells. Statistics. Mean values and SD were compared using an unpaired student's t-test, with Welch's correction in the case of nonhomogeneous variances.
  • mice with 100 ⁇ g LPS or 200 ⁇ g LPS i.p. mice pretreated with ZnSO 4 in the drinking water were significantly protected.
  • mice pretreated with ZnSO 4 in the drinking water were significantly protected Figure 1.
  • Figure 2 We found that within 24 h, all control mice had died.
  • mice 8/12 2/13 ** p 0.0045

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur la découverte de l'utilité du traitement au zinc, combiné au facteur onconécrosant (TNF) et/ou interféron-gamma (IFN-η) dans la destruction considérable d'une tumeur et la protection complète contre un choc léthal induit par TNF. L'invention porte également sur l'utilisation du zinc dans la prévention et/ou le traitement de maladies, et plus spécifiquement dans le traitement ou la prévention d'un pathologie induite par TNF.
PCT/EP2002/005222 2001-05-08 2002-05-07 Utilisation du zinc dans la prevention d'une pathologie induite par tnf pendant une therapie contre le cancer WO2002089919A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01201656.4 2001-05-08
EP01201656 2001-05-08

Publications (2)

Publication Number Publication Date
WO2002089919A2 true WO2002089919A2 (fr) 2002-11-14
WO2002089919A3 WO2002089919A3 (fr) 2003-02-20

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015281A1 (fr) * 1996-10-08 1998-04-16 Hartford Hospital Provocation d'une reaction au stress cellulaire au moyen de sels de metaux lourds
WO2001000193A2 (fr) * 1999-06-23 2001-01-04 Zinc Therapeutics Canada, Inc. Ionophores de zinc utilises comme agents anti-apoptose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015281A1 (fr) * 1996-10-08 1998-04-16 Hartford Hospital Provocation d'une reaction au stress cellulaire au moyen de sels de metaux lourds
WO2001000193A2 (fr) * 1999-06-23 2001-01-04 Zinc Therapeutics Canada, Inc. Ionophores de zinc utilises comme agents anti-apoptose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KLOSTERHALFEN B ET AL: "Influence of heat shock protein 70 and metallothionein induction by zinc-bis-(DL-hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia." BIOCHEMICAL PHARMACOLOGY, vol. 52, no. 8, 1996, pages 1201-1210, XP001120173 ISSN: 0006-2952 cited in the application *
WAELPUT W ET AL: "A MEDIATOR ROLE FOR METALLOTHIONEIN IN TUMOR NECROSIS FACTOR-INDUCED LETHAL SHOCK" JOURNAL OF EXPERIMENTAL MEDICINE, TOKYO, JP, vol. 194, no. 11, 3 December 2001 (2001-12-03), pages 1617-1624, XP001077722 ISSN: 0022-1007 *

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