WO2021121277A1 - Procédé et composition pour le traitement d'un cancer - Google Patents

Procédé et composition pour le traitement d'un cancer Download PDF

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Publication number
WO2021121277A1
WO2021121277A1 PCT/CN2020/136849 CN2020136849W WO2021121277A1 WO 2021121277 A1 WO2021121277 A1 WO 2021121277A1 CN 2020136849 W CN2020136849 W CN 2020136849W WO 2021121277 A1 WO2021121277 A1 WO 2021121277A1
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Prior art keywords
composition
combination
use according
cancer
isolated
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PCT/CN2020/136849
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English (en)
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Mei-Nan Tuan
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Tuan Mei Nan
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Publication of WO2021121277A1 publication Critical patent/WO2021121277A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/335—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
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Staphylococcal enterotoxins are representative of a family of proteins, also named as superantigens (SAg) , which cause non-specific activation of T lymphocytes (T-cells) resulting in polyclonal T cell activation and massive cytokine release.
  • SAg superantigens
  • Superantigens are produced by various microorganisms like pathogenic bacteria, mycoplasma or viruses, most likely as a defense mechanism against the immune system.
  • SEs are capable of activating up to 20%of the body’s T-cells. SEs are known as the most powerful T-cell mitogens.
  • the present invention provides a method for treatment of a cancer comprising administering to a subject in need thereof a Staphylococcal enterotoxin (SE) at an amount effective to lead to a tumoricidal effect in the subject.
  • SE Staphylococcal enterotoxin
  • FIG. 3 shows the effects of SE in different concentrations in inducing human T cell IFN- ⁇ release. Histogram of IFN- ⁇ secreting SFC (IFN- ⁇ SFC) in PBMCs induced by SE with different concentrations. ConA (10 mg/ml) was used as a positive control. The IFN- ⁇ SFC numbers were assayed by ELISPOT and results were shown as means ⁇ standard errors.
  • Figure 4 shows the numbers of WBC (A) and lymphocytes (B) after the administration of 5-FU in a combination of G-CSF or SE, as compared with a blank and 5-FU alone.
  • subject refers to a person, multiple persons, and animals.
  • the invention features a composition comprising SE potentially.
  • concentration of SE may be in the range of 0.01-100 ng/ml.
  • the composition of the invention provides an efficacy to evoke T cell tumoricidal function. It is proven that the composition of the invention is beneficial to cancer patients treated with chemotherapy or radiotherapy. Accordingly, the combination or composition may be used as a chemotherapeutic or radiotherapeutic adjuvant for treating malignancies.
  • the active ingredients may be isolated from plant extracts containing polyphenolic compounds and flavonoids such as oligomeric proanthocyanidins, Quercetin, Hesperidin, Genstein, Daidzein and Resveratrol, which have generally been shown to provide benefit in anti-inflammatory effects. Other effects reported in many studies show that these active ingredient provide the effect for prevention of a disease in animal experiments. For example, small doses (0.02–8 mg/kg) of Resveratrol given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens.
  • flavonoids such as oligomeric proanthocyanidins, Quercetin, Hesperidin, Genstein, Daidzein and Resveratrol
  • Vitamin C (Molecular Formula: C 6 H 8 O 6 ; Molecular Weight: 176.12) may be isolated from kakadu plum, camu camu, rose hip, acerola, sea buckthorn, jujube, baobab, blackcurrant, red pepper, parsley, guava, lemon, or kiwifruit.
  • Enzyme-linked immunospot (ELISPOT) assay was performed to assess the number of IFN- ⁇ secreting PBMCs.
  • Human peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats obtained from healthy blood donors by Ficoll-Paque (Amersham, Sweden) density gradient centrifugation. Cells were washed three times with sterile PBS and resuspended in complete RPMI-1640 or DMEM culture medium with 10%FCS or FBS. Cell counting was performed using hemocytometer and trypan blue staining. PBMCs were adjusted to different concentrations and cultured at optimal conditions.
  • Peripheral bloods were collected from orbital plexus before every injection and anti-coagulated with 20 U/ml sodium heparin. Cells were washed with PBS for three times after lysis with lysis buffer and then stained with PE conjugated anti-mouse CD4 + and FITC-conjugated anti-mouse CD8 + antibodies at 4°C for 30 minutes. After washing the cells with PBS again, samples were fixed with fixation solution, and analyzed on a FAC Scalibur TM flow cytometer (BD Biosciences) with CELLQuest TM software.
  • the purified SE protein was used to stimulate PBMC proliferation.
  • BSA and PHA-P were used as negative and positive controls, respectively (see Figure 2) .
  • the experimental data showed that the stimulation of PBMC proliferation by SE protein is very efficient even at the concentration of 50 ng/ml (see Figure 3) .
  • Superantigen induced tumoricide via activating T cells The present invention relates SE could lead T cell to this direction.
  • Mouse is less sensitive to superantigen, yet C57BL/6 mouse has been repeatedly employed successfully to investigate SEs superantigenic activity. Due to the less sensitivity, the injected SE doses were relative high, i.e. 125 mg/kg, 250 mg/kg, 500 mg/kg. After the injection, peripheral bloods were collected from orbital plexus and red blood cells were removed. In flow cytometry, cells double stained with anti-mouse CD4 + and CD8 + specific fluorescent antibodies were analyzed (see Table 1) . In each dose group, both CD4 + and CD8 + T cells expanded in a time dependent manner, but not with the same slope. The higher the dose was, the slower the slope was.
  • SE induces activation of mice CD4+ and CD8+ T lymphocytes in vivo.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Mycology (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Botany (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement d'un cancer, comprenant l'administration à un sujet qui en a besoin d'une entérotoxine staphylococcique avec ou sans un ou plusieurs principes actifs choisis dans le groupe constitué par des proanthocyanidines oligomères, de la quercétine, de l'hespéridine, de la génistéine, de la daidzéine et du révératrol. L'invention concerne également une composition pour le traitement d'un cancer comprenant une entérotoxine staphylococcique.
PCT/CN2020/136849 2019-12-16 2020-12-16 Procédé et composition pour le traitement d'un cancer WO2021121277A1 (fr)

Applications Claiming Priority (2)

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US201962948382P 2019-12-16 2019-12-16
US62/948,382 2019-12-16

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WO2021121277A1 true WO2021121277A1 (fr) 2021-06-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4378469A1 (fr) * 2022-12-02 2024-06-05 Lietuvos Sveikatos Mokslu Universitetas Utilisation de fractions de proanthocyanidine obtenues à partir de feuilles et de fruits de lingonberry pour la préparation de sphéroïdes de cellules cancéreuses et leurs effets dans les cellules cancéreuses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6126945A (en) * 1989-10-03 2000-10-03 Pharmacia Ab Tumor killing effects of enterotoxins, superantigens, and related compounds
WO2008127298A2 (fr) * 2006-10-24 2008-10-23 Subroto Chatterjee Compositions de peptide d'entérotoxine b staphylococcique et procédés d'utilisation
CN101391096A (zh) * 2007-09-19 2009-03-25 中国人民解放军军事医学科学院微生物流行病研究所 葡萄球菌肠毒素c在制备肿瘤治疗药物中的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6126945A (en) * 1989-10-03 2000-10-03 Pharmacia Ab Tumor killing effects of enterotoxins, superantigens, and related compounds
WO2008127298A2 (fr) * 2006-10-24 2008-10-23 Subroto Chatterjee Compositions de peptide d'entérotoxine b staphylococcique et procédés d'utilisation
CN101391096A (zh) * 2007-09-19 2009-03-25 中国人民解放军军事医学科学院微生物流行病研究所 葡萄球菌肠毒素c在制备肿瘤治疗药物中的用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FRANK G.E. PERABO, PATRICIA L. WILLERT, ANDREAS WIRGER, DORIS H. SCHMIDT, EVA WARDELMANN, MARIO SITZIA, ALEXANDER VON RUECKER, STE: "Preclinical evaluation of superantigen (Staphylococcal Enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer，", INTERNATIONAL JOURNAL OF CANCER, vol. 115, no. 4, 18 April 2005 (2005-04-18), pages 591 - 598, XP055821563, ISSN: 0020-7136, DOI: 10.1002/ijc.20941 *
HU LU-WEN: "Research Progress of Cyclodextrin and Its Derivatives in Anti-tumor Natural Active Ingredients", STRAIT PHARMACEUTICAL JOURNAL, vol. 31, no. 11, 15 November 2019 (2019-11-15), pages 13 - 18, XP055821603, ISSN: 1006-3765 *
KENNETH A NEWELL, ELLENHORN JOSHUA D I, BRUCE DAVID S, BLUESTONEMII JEFFREY A: "In vivo T-cell activation by staphylococcal enterotoxin B prevents outgrowth of a malignant tumor", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 88, no. 3, 1 February 1991 (1991-02-01), pages 1074 - 1078, XP055821559, DOI: 10.1073/pnas.88.3.1074 *
WENBIN ZHAO , YANGYANG LI , WENHUI LIU , DING DING , YINGCHUN XU , LIQIANG PAN , SHUQING CHEN: "Transcytosis， Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug，", TOXINS, vol. 8, no. 6, 185, 16 June 2016 (2016-06-16), pages 1 - 12, XP055821571, ISSN: 2072-6651, DOI: 10.3390/toxins8060185 *
ZHAO WEN-ZHI ET AL.，: "The anti-tumor mechanism of vitamin C，", ELECTRON. J. METAB. NUTR. CANCER，, vol. 6, no. 4, 9 December 2019 (2019-12-09), pages 409 - 414 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4378469A1 (fr) * 2022-12-02 2024-06-05 Lietuvos Sveikatos Mokslu Universitetas Utilisation de fractions de proanthocyanidine obtenues à partir de feuilles et de fruits de lingonberry pour la préparation de sphéroïdes de cellules cancéreuses et leurs effets dans les cellules cancéreuses

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