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WO2010028503A1 - Utilisation d'une protéine dérivée du lactosérum riche en cystéine chez des patients sous chimiothérapie ou radiothérapie afin d'améliorer leur survie - Google Patents

Utilisation d'une protéine dérivée du lactosérum riche en cystéine chez des patients sous chimiothérapie ou radiothérapie afin d'améliorer leur survie Download PDF

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Publication number
WO2010028503A1
WO2010028503A1 PCT/CA2009/001277 CA2009001277W WO2010028503A1 WO 2010028503 A1 WO2010028503 A1 WO 2010028503A1 CA 2009001277 W CA2009001277 W CA 2009001277W WO 2010028503 A1 WO2010028503 A1 WO 2010028503A1
Authority
WO
WIPO (PCT)
Prior art keywords
cysteine
protein
patients
cancer
rich
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/CA2009/001277
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English (en)
Inventor
Dr. Wulf Droge
Dr. Gustavo Bounous
John H. Monson
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.)
2458781 Canada Inc
Original Assignee
2458781 Canada Inc
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
Priority claimed from US12/210,030 external-priority patent/US20100069288A1/en
Priority claimed from CA002639562A external-priority patent/CA2639562A1/fr
Application filed by 2458781 Canada Inc filed Critical 2458781 Canada Inc
Publication of WO2010028503A1 publication Critical patent/WO2010028503A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to a cysteine-rich protein formulation and its use in the treatment of cancer patients to improve patient survival and quality of life.
  • cancer cachexia results to some extent from aberrant inflammation (13, 15) and is significantly correlated with an oxidative shift in plasma redox status, as indicated by a decreased ratio of reduced to oxidized cysteine (16).
  • Bounous et al had previously disclosed anti-cancer therapeutic compositions containing whey protein concentrate, wherein increasing cellular GSH protected target cells against the effects of a carcinogen (U.S. 5,888,552).
  • the whey protein concentrate was shown useful in methods for treating cancer.
  • the inventors believed that the increased availability of substrate for GSH synthesis, due to undenatured whey protein delivering glutamyl cysteine, a potent cysteine delivery system, is involved in inhibition of replication of formed cancer cells.
  • concern has been expressed that antioxidative treatment may interfere with these therapies and thus exacerbate mortality (see 9, 4, 24).
  • cysteine is a limiting biosynthetic precursor of glutathione (GSH) 1 it is expected to ameliorate the oxidative stress.
  • the inventors have determined that a cysteine-rich undenatured whey-derived protein formulation did not interfere with the tumor-cytotoxic effects of chemotherapy and radiation therapy and this did not have a negative effect on the clinical outcome, that is, negatively affect survival and increase mortality, as feared by some. Indeed, the inventors have discovered that use of a high-cysteine undenatured whey derived protein in the treatment of cancer patients resulted in an increase in patient survival.
  • the present invention is directed to a cysteine-rich undenatured whey derived protein and formulations thereof for use in treatment of cancer patients, to improve patient survival.
  • the invention relates to a dosage of a cysteine-rich whey derived protein in a range about 5 to 30 grams of protein per day, preferably in a range of about 5-25 g/day, more preferably about 13-20 g/day and most preferably about 13 g/day.
  • the present invention relates to the use of a cysteine-rich whey derived protein in the treatment of cancer patients and methods of treatment using the said protein, to improve patient survival, along with other indicia of quality of life, particularly in use with patients undergoing chemotherapy, radiation therapy or both; and the use of said cysteine-rich protein to prepared formulations or medicaments for such use.
  • Figure 1 Trial profile of the casein group and cysteine-rich protein group.
  • Figure 2 Kaplan-Meier survival curves of the lung cancer patients.
  • the inventors have determined that a cysteine-rich undenatured whey derived protein and formulations thereof improves patient survival for patients undergoing chemotherapy and radiation therapy.
  • casein was replaced with a high-cysteine whey- derived protein formulation.
  • the present inventors investigated if patient survival may be ameliorated in cancer patients, along with other quality of life, indicia, such as body weight loss and body cell mass, by the high-cysteine whey-derived protein formulation compared with casein.
  • Casein i.e., the protein base of the majority of clinically used enteral nutritional supplements
  • cysteine is a limiting biosynthetic precursor of GSH, it is expected to ameliorate the oxidative stress.
  • the high-cysteine whey derived protein was designed to have an even higher cysteine content than normal whey protein (see Table 1).
  • TaWe 1 Amino acid composition* of the cysteine-rich protein (Cy ⁇ P) and the control protein (casein).
  • Body cell mass (kg) 22.5 ⁇ 6.8 22.4 ⁇ 4.6
  • TNF ⁇ (pg/mL) 15.5 ⁇ 52.3 t ⁇ 2. ⁇ 1.7* ⁇ (10.4 ⁇ 38.5) ⁇ (2.6 ⁇ 1.5) ⁇ IL-6 (pg/mL) 6.2 ⁇ 3.9 4.6 ⁇ 3.3
  • Body cell mass +10.34 ⁇ 14.10 +14.09 ⁇ 15.84 ⁇ -5.47 ⁇ 34.63 n +11.55118.0S* 1 ** -2.85 ⁇ 30.93 H +8 ⁇ 4 ⁇ 17.89**
  • results show that the survival of non-small cell lung cancer patients with chemotherapy or radiotherapy or both was not decreased by supplementation with the cysteine-rich protein. Indeed, the results show that patient survival improved by supplementation with the cysteine-rich protein derived from undenatured whey. The results thus not only alleviate the concern that treatment with certain antioxidants may interfere with the tumor-cytotoxic effects of chemotherapy and radiotherapy and thus increase mortality (see
  • the whey-derived protein was especially designed to have an even higher cysteine content than normal whey protein, and cysteine is a biosynthetic precursor not only of proteins but also of the cellular antioxidant, glutathione.
  • cysteine is a biosynthetic precursor not only of proteins but also of the cellular antioxidant, glutathione.
  • This paradigm links the differential effects of the two proteins in our trial to established molecular mechanisms. The trial confirmed an important prediction of the hypothesis. Oxidative stress has also been implicated in the adverse effects of chemotherapy and radiotherapy (4, 9, 19, 23).
  • the study medication was administered in conjunction with standard of care for cancer type and stage.
  • Redblood cells were obtained from 0.5 ml blood by centrifugation for 5 min at
  • precipitation reagent aqueous solution of trichloroacetic acid
  • the statistical analysis was performed by an independent statistical company (Boreal Primum, Montreal, Quebec). The data were analyzed separately for the two strata (disease sites) and expressed as means ⁇ SD. Treatment effects were statistically evaluated by comparison with the control group (two- sided t test for independent variables, if not indicated otherwise) and by comparison with the corresponding baseline values (t test for dependent variables). Comparison of the treatment groups was based on the data obtained at 6 months or on the last-observation-carried-forward (LOCF) method for patients who completed at least two visits. Survival curves were generated with the use of Kaplan-Meier estimates for treatment and compared with the log-rank test. Hazard ratios (HRs) were estimated by using a Cox proportional-hazard model. The results were judged by the p value. A p value ⁇ 0.05 was regarded as statistically significant.
  • Glare P Clinical predictors of survival in advanced cancer. J Support Oncal 3: 331-339, 2005.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Une formulation à base d'une protéine dérivée du lactosérum non dénaturée et riche en cystéine n'interfère pas avec les effets cytotoxiques antitumoraux de la chimiothérapie et de la radiothérapie et n'a pas d'effet négatif sur le pronostic clinique, à savoir qu'elle n'affecte pas défavorablement la survie ni n'augmente la mortalité. En effet, l'usage d'une protéine dérivée du lactosérum non dénaturée et riche en cystéine pour traiter des patients cancéreux a permis d'augmenter la survie des patients.
PCT/CA2009/001277 2008-09-12 2009-09-11 Utilisation d'une protéine dérivée du lactosérum riche en cystéine chez des patients sous chimiothérapie ou radiothérapie afin d'améliorer leur survie Ceased WO2010028503A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA2,639,562 2008-09-12
US12/210,030 US20100069288A1 (en) 2008-09-12 2008-09-12 Use of cysteine-rich whey derived protein in patients receiving chemotherapy or radiotherapy to improve patient survival
US12/210,030 2008-09-12
CA002639562A CA2639562A1 (fr) 2008-09-12 2008-09-12 Utilisation de proteines derivees de lactoserum riche en cysteine chez des patients subissant une chimiotherapie ou une radiotherapie pour ameliorer leur chance de survie

Publications (1)

Publication Number Publication Date
WO2010028503A1 true WO2010028503A1 (fr) 2010-03-18

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Family Applications (1)

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PCT/CA2009/001277 Ceased WO2010028503A1 (fr) 2008-09-12 2009-09-11 Utilisation d'une protéine dérivée du lactosérum riche en cystéine chez des patients sous chimiothérapie ou radiothérapie afin d'améliorer leur survie

Country Status (3)

Country Link
AR (1) AR073585A1 (fr)
TW (1) TWI515005B (fr)
WO (1) WO2010028503A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163796B1 (en) 2009-07-28 2012-04-24 BioChemical Solutions, LLC Treatment of cancer by oxidation-reduction potentiation of cancerostatic dicarbonyls
CN103269697A (zh) * 2010-10-21 2013-08-28 雀巢产品技术援助有限公司 半胱氨酸和食物摄入
IT201800005714A1 (it) * 2018-05-25 2019-11-25 Concentrato di proteine di siero del latte in associazione con trattamento antitumorale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374390A1 (fr) * 1988-12-23 1990-06-27 Immunotech Research Corporation Ltd. Composition de protéines de petit lait, procédé de production et application de la composition de protéines de petit-lait

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374390A1 (fr) * 1988-12-23 1990-06-27 Immunotech Research Corporation Ltd. Composition de protéines de petit lait, procédé de production et application de la composition de protéines de petit-lait

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BARUCHEL, S. ET AL.: "In vitro selective modulation of cellular glutathione by a humanized native milk protein isolate in normal and rat mammary carcinoma model.", ANTICANCER RES., vol. 16, no. 3A, 1996, pages 1095 - 1099 *
BOUNOUS, G.: "Whey protein concentrate (WPC) and glutathione modulation in cancer treatment.", ANTICANCER RES., vol. 20, 2000, pages 4785 - 4792 *
KENNEDY, R. S ET AL.: "The use of whey protein concentrate in the treatment of patients with metastatic carcinoma: A phase I-II clinical trial.", ANTICANCER RES., vol. 15, no. 6B, 1995, pages 2643 - 2649 *
MARSHALL, K.: "Therapeutic applications of whey protein.", ALTERNATIVE MED. REV., vol. 9, no. 2, 2004, pages 136 - 155 *
PARODI, P.W.: "Role for milk proteins and their peptides in cancer prevention.", CURR. PHARM. DESIGN, vol. 13, no. 8, 2007, pages 813 - 828 *
TSAI, W.Y. ET AL.: "Enhancing effect of patented whey protein isolate (Immunocal) on cytotoxicity of an anticancer drug.", NUTRITION AND CANCER, vol. 38, no. 2, 2000, pages 200 - 208 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163796B1 (en) 2009-07-28 2012-04-24 BioChemical Solutions, LLC Treatment of cancer by oxidation-reduction potentiation of cancerostatic dicarbonyls
CN103269697A (zh) * 2010-10-21 2013-08-28 雀巢产品技术援助有限公司 半胱氨酸和食物摄入
EP2629769A1 (fr) 2010-10-21 2013-08-28 Nestec S.A. Cystéine et prise alimentaire
US9233090B2 (en) 2010-10-21 2016-01-12 Nestec S.A. Cysteine and food intake
EP2629769B1 (fr) * 2010-10-21 2017-10-04 Nestec S.A. Cystéine et l'anorexie liée à l'âge
IT201800005714A1 (it) * 2018-05-25 2019-11-25 Concentrato di proteine di siero del latte in associazione con trattamento antitumorale
WO2019224710A1 (fr) * 2018-05-25 2019-11-28 Lb Lyopharm S.R.L. Concentré de protéines lactosériques en association avec un traitement antitumoral

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Publication number Publication date
TWI515005B (zh) 2016-01-01
AR073585A1 (es) 2010-11-17
TW201014599A (en) 2010-04-16

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