WO1999027947A1 - Utilisation de preparations de lectine pour lutter contre des cancers de la vessie - Google Patents

Utilisation de preparations de lectine pour lutter contre des cancers de la vessie Download PDF

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Publication number
WO1999027947A1
WO1999027947A1 PCT/EP1998/007512 EP9807512W WO9927947A1 WO 1999027947 A1 WO1999027947 A1 WO 1999027947A1 EP 9807512 W EP9807512 W EP 9807512W WO 9927947 A1 WO9927947 A1 WO 9927947A1
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WO
WIPO (PCT)
Prior art keywords
mistletoe
bladder
cells
extract
preparations
Prior art date
Application number
PCT/EP1998/007512
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German (de)
English (en)
Inventor
Hans Lentzen
Ulrich Mengs
Klaus Weber
Original Assignee
Madaus Ag
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 Madaus Ag filed Critical Madaus Ag
Priority to AU14885/99A priority Critical patent/AU1488599A/en
Publication of WO1999027947A1 publication Critical patent/WO1999027947A1/fr

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Classifications

    • 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
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • 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 invention relates to the use of ectin preparations for the treatment of tumor diseases of the urinary bladder.
  • Bladder cancer is one of the most common urological tumors with an ever increasing number of cases. Superficial bladder tumors make up about 70% of all newly diagnosed cases. " Even if the 3las carcinomas are surgically removed, the risk of tumor recurrence remains very high. This is often accompanied by a further progression of the disease. Although the frequency of recurrences depends on the depth of infiltration into the surrounding tissue and the degree of differentiation of the Tumors, but in two thirds of all cases tumors can be expected to recur within 5 years.
  • Bacillus Caimette-Guerin is the most frequently used therapy for the treatment of superficial bladder carcinomas and for the prevention of relapses after surgical removal of the primary tumors.
  • the intravesical application has proven to be advantageous here, since it enables better contact between intratumoral immune cells and BCG than with systemic therapy.
  • the mechanism of action of BCG has not yet been elucidated in detail, but it is believed that the effect occurs through activation of the immune system.
  • the poor tolerance of BCG has proven to be a major disadvantage of this therapy (D. Lamm et al .; J. Uroi. 144 ' 1990) 1328; D. Lamm et al. , J. Uroi. 147 (1992) 596.
  • mistletoe Viscum albumj has long been known as a medicinal plant. Aqueous extracts from the mistletoe have been used for decades for systemic non-specific stimulation of the immune system in creostneriaia. As active substances are veromdun ⁇ en from the Substance class of the lectures, the misectectives I, II and III have been recognized (T. Hajto et al., Cancer Res. 49 (1989), 4803; J. Beuth et ai., Arzneistoff. -Forscn. 43 (1993), 166) .
  • Misteie extracts are able to stimulate the release of immunocompromising cytokymes such as Interieukin 1 (IL-I, Interieukm 6 (IL-6), Interferon- ⁇ (IFN- ⁇ ) and Tumor Necrosis Factor (TNF-) (T. Haito et al., 1986, Oncoiogy 43: 93).
  • immunocompromising cytokymes such as Interieukin 1 (IL-I, Interieukm 6 (IL-6), Interferon- ⁇ (IFN- ⁇ ) and Tumor Necrosis Factor (TNF-) (T. Haito et al., 1986, Oncoiogy 43: 93).
  • RIP-2 type double-chain ibosomene-inacting proteins 1 such as the Ricme available from Eupnorbiaceen and those from Fabaceer. (Abrus precatonus) originating and those from Pasifloraceae (Adenia digitataj Isoiieroaren Modeccme and especially mispartectme have the ability to activate unspecific defense mechanisms and thereby induce a clinically relevant immune modulation.
  • the components of the immune system which are crucial for the defense against malignant cells are those Natural killer cells (NK cells;, T cells, 3 cells, monocytes, macrophages and dendritic cells.
  • Misteie extracts which are standardized on active mists, can dose-dependently dose-dependent clinically relevant immune parameters. Such extracts also show a significant reduction in lung and liver metastases after subcutaneous administration in m-vivo studies with BALB / c mice and other tumor models (Ll sarcoma and RAW 117-H 10 lympnosarcoma) and thus show their antitumor efficacy by J. Beuth , Z. All. Med. 70 (1994! 159).
  • mistletoe extract preparations advantageously have both immunostimulatory and cytotoxic effects, as can be demonstrated in animal models.
  • Aqueous extracts (1: 1.1-1.5) from uncultivated mistletoe branches with leaves or lectin concentrates from mistletoe extracts according to EP 602 686 or standardized, stabilized mistletoe extract preparations according to DE 195 48 367 are used as mistletoe extract preparations.
  • Mistletoe lectins belong to the glycoprotein class of substances and consist of a lighter subunit (A chain) with ri-bosome-inactivating properties and a heavier subunit (B chainj), which is characterized by specific sugar-binding activity.
  • the subunits are linked to one another via disulfide bridges
  • the A-chain of mistletoe lectin has partially hydrophobic properties and has a high ability to bind membranes, so that when used locally, the mistletoe extract preparation is rapidly absorbed from the aqueous environment of the bladder contents into the tumor-bearing tissue of the bladder.
  • Misteiiectin I and mistletoe extract preparations standardized to misteiiectin are able to increase the release of cytokines from PBM cells (peripheral biood mononuclear cells) such as TNF-, Interieukin 1 and Interieukin 6.
  • cytokines from PBM cells (peripheral biood mononuclear cells) such as TNF-, Interieukin 1 and Interieukin 6.
  • the activity of the natural cell lines is stimulated via the various cytokines, the effect of which can be measured as cytotoxic activity against the bladder cancer cells.
  • the cytotoxic activity was determined as a line-mediated lysis using an MTT (3 -14, 5-dimethyithiazoi-2-yij-2, 5-diphenyitetrazoium bromide) assay. Exponentially growing Fen cells were treated with trypsin (2.5%) plus EDTA (0.2%) for 10 minutes, washed, resuspended in nutrient medium and placed on microtiter plates. After 24 hours the cell culture was washed and the effector cells (PBMC) were placed in the same medium so that the ratio of effector cells and target lines was 40: 1.
  • MTT 5-dimethyithiazoi-2-yij-2, 5-diphenyitetrazoium bromide
  • the cocuitures were incubated for 4 hours with or without Misteiiectin I and a further 2 hours after the addition of MTT in a final concentration of 0.16 mg / ml. The supernatant was discarded and after the addition of isopropanol and acetic acid, the optical density of the clear formazan formed by mitochondrial enzymes of the living cells was measured after 30 minutes.
  • the line-mediated lysis (in%) was calculated using the following formula:
  • OD EZ optical density from the co-culture of effector and target lines
  • OD E optical density of the cultures of effector or target lines alone, each with or without misteictin I.
  • the human 3-line tumor epithermal line FEN was developed by Dr. AME Nouri (The Royal London Hospital, Department of Medical Oncoiogy, London, UK).
  • the cells were cultivated in MDC-I medium (PAN-Syste s GmbH, Aidenbach, Germany) at 37 ° C. and 5% CO 2 in a fumigation incubator.
  • MDC-I medium PAN-Syste s GmbH, Aidenbach, Germany
  • 150 ⁇ i of a suspension of FEN cells 1.5 ⁇ 10 5 cells / ml
  • the mistletoe extract preparation or the control solution was added.
  • an anti-mistletoe lectin antiserum (batch no.
  • Mistle extract preparations can be aqueous extracts from mistletoe plants, lectem concentrates from mistletoe extracts and corresponding standardized, stoilized mistletoe extract preparations and standardized, stabilized aqueous extracts from mistletoe branches with leaves.
  • Ampoules containing 5 ml of solution containing 500 ng of active mistiiectin are used as the dosage form.
  • the metering is carried out by producing a pnysioiogiscnen Kocnsaiz solution of 50 ml, which can contain 500 ng to 6000 ng active Misteiiectin in the form of the aqueous extract.
  • the 50 ml of this solution are orchestrated into the bladder by intravenous instillation and take up to one to four hours there.
  • the treatment takes place once per wokne over smaller woknen ⁇ inwe ⁇ .
  • the described concentrations of manure extract preparation are well tolerated and the risk of side effects is minimized.
  • intravenous formulations can contain well-tolerated auxiliaries such as ethanoi, methylpyrrolidone, polyethylene glycol, oley alcohol, octanoi, linoleic acid, propylene glycol kocerlycerol or dimethyl sulfoxide.
  • auxiliaries such as ethanoi, methylpyrrolidone, polyethylene glycol, oley alcohol, octanoi, linoleic acid, propylene glycol kocerlycerol or dimethyl sulfoxide.
  • Stabilizers such as alkanoia, in particular poiyoie and carbohydrates, hydrophilic polymers, in particular polyvinyl pyrrolidone, polyvinyl alcohol, nonionic surfactants such as polyalkylene glycol and polyoxyethylene fatty acid esters or proteins such as albumin may also be necessary for the preparation of the desired formulation.
  • Figure 1 shows the mating rate of mice treated with various concentrations of mistletoe extract preparations after induction of bladder carcinoma for several weeks compared to an untreated control group.
  • Figure 2 shows the proportion of mice still bearing tumors after treatment compared to the untreated control group.
  • Figure 3 shows the proportion of mice in which metastases were still found after treatment compared to the untreated control group.
  • Figure 4 shows the cell-mediated cytotoxic activity of human PBM cells against the Fen-urinary cancer cell line in vitro with or without exposure to misteiiectin I.
  • Figure 5 shows the vitality (number of metabolically active cells) of human bladder carcinoma cells under the action of the mist extract extract and under the action of a combination of mist extract extract and an antiserum which acts against mistei extract.

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

Abstract

L'invention concerne l'utilisation de préparations d'extrait avec des lectines du type RIP-2, notamment de la lectine de gui, pour traiter des cancers de la vessie, pour prévenir la formation de métastases et pour éviter des récidives, en vue de compléter le traitement chirurgical.
PCT/EP1998/007512 1997-11-27 1998-11-21 Utilisation de preparations de lectine pour lutter contre des cancers de la vessie WO1999027947A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14885/99A AU1488599A (en) 1997-11-27 1998-11-21 The use of lectin preparations for combating cancers of the bladder

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19752597A DE19752597A1 (de) 1997-11-27 1997-11-27 Verwendung von Lektinzubereitungen bei der Bekämpfung von Harnblasenkarzinomen
DE19752597.0 1997-11-27

Publications (1)

Publication Number Publication Date
WO1999027947A1 true WO1999027947A1 (fr) 1999-06-10

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/007512 WO1999027947A1 (fr) 1997-11-27 1998-11-21 Utilisation de preparations de lectine pour lutter contre des cancers de la vessie

Country Status (4)

Country Link
AU (1) AU1488599A (fr)
DE (1) DE19752597A1 (fr)
WO (1) WO1999027947A1 (fr)
ZA (1) ZA9810815B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3243523A1 (fr) * 2016-05-11 2017-11-15 YACARE GmbH Lectine et prophylaxie du cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2508195A1 (fr) 2011-04-06 2012-10-10 Cytavis BioPharma GmbH Médicament comprenant des lectines de gui recombinantes pour le traitement du mélanome malin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4496539A (en) * 1982-02-01 1985-01-29 Massachusetts Institute Of Technology Method for treating cancer using galactose-specific lectins
DE3825186A1 (de) * 1988-03-28 1989-03-16 Ta Cheng Tung Oral verabreichbare, lektine enthaltende zubereitungen zur behandlung von metastasen
EP0652231A1 (fr) * 1993-03-02 1995-05-10 Universidad De Valladolid PROTEINES INACTIVATRICES DE RIBOSOMES (RIPs) A DEUX CHAINES NON TOXIQUES, PROCEDE POUR LEUR PREPARATION ET APPLICATIONS
WO1997011967A1 (fr) * 1995-09-27 1997-04-03 Thomas David Extrait de viscum album (gui)
DE19548367A1 (de) * 1995-12-27 1997-07-03 Madaus Ag Immunologisch wirksame Mistelextraktzubereitungen

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4496539A (en) * 1982-02-01 1985-01-29 Massachusetts Institute Of Technology Method for treating cancer using galactose-specific lectins
DE3825186A1 (de) * 1988-03-28 1989-03-16 Ta Cheng Tung Oral verabreichbare, lektine enthaltende zubereitungen zur behandlung von metastasen
EP0652231A1 (fr) * 1993-03-02 1995-05-10 Universidad De Valladolid PROTEINES INACTIVATRICES DE RIBOSOMES (RIPs) A DEUX CHAINES NON TOXIQUES, PROCEDE POUR LEUR PREPARATION ET APPLICATIONS
WO1997011967A1 (fr) * 1995-09-27 1997-04-03 Thomas David Extrait de viscum album (gui)
DE19548367A1 (de) * 1995-12-27 1997-07-03 Madaus Ag Immunologisch wirksame Mistelextraktzubereitungen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GABIUS, HANS JOACHIM ET AL: "Scientific verification of mistletoe therapy", PHARM. ZTG. (1994), 139(22), 9-14, XP002099484 *
LIN J Y ET AL: "Studies on the antitumor lectins isolated from the seeds of Ricinus communis (castor bean).", TOXICON, (1986) 24 (8) 757-65, XP002099483 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3243523A1 (fr) * 2016-05-11 2017-11-15 YACARE GmbH Lectine et prophylaxie du cancer

Also Published As

Publication number Publication date
DE19752597A1 (de) 1999-06-10
ZA9810815B (en) 1999-05-31
AU1488599A (en) 1999-06-16

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