EP1047433A1 - Cellulose derivatives and colorectal cancer risk reduction - Google Patents
Cellulose derivatives and colorectal cancer risk reductionInfo
- Publication number
- EP1047433A1 EP1047433A1 EP99903303A EP99903303A EP1047433A1 EP 1047433 A1 EP1047433 A1 EP 1047433A1 EP 99903303 A EP99903303 A EP 99903303A EP 99903303 A EP99903303 A EP 99903303A EP 1047433 A1 EP1047433 A1 EP 1047433A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fiber
- fermentable
- methylcellulose
- soluble
- cellulose
- 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- Withdrawn
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/717—Celluloses
-
- 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 directed to the risks associated with colorectal cancers and dietary components.
- Colorectal cancer is a common and serious medical condition.
- the incidence of colon cancer is roughly the same in men and women; rectal cancer is somewhat more common in men.
- Epidemiological studies have shown that when populations have migrated from areas of low incidence (e.g., Eastern Europe or Asia) to an area of higher incidence (the U.S.), their incidence of colorectal cancers increases to U.S. rates within 10-15 years. This suggests that dietary factors play a role in the incidence of colorectal cancers.
- various epidemiological studies which have attempted to relate diet composition to relative risk of colon cancer. Dietary fat intake appears to be positively correlated to risk. Dietary fiber also appears to play a role, although this may not be true for all types of fiber.
- the present invention is to a method of reducing the incidence of colorectal cancers in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a water soluble, non-fermentable cellulose derivative, alone or in combination with an insoluble fiber and/or a soluble fermentable fiber.
- cellulose derivatives have properties which are unique relative to the naturally occurring food fibers. They are 100% water soluble (in cool water; they become insoluble in hot water), and they are non-fermentable.
- Naturally occurring soluble fibers such as pectin, psyllium, and guar gum, are fermentable in the human GI tract, essentially completely in the case of pectin or guar, and to a significant extent (-50%) in the case of psyllium.
- the fermentation products particularly the short chain fatty acid butyrates, may be responsible for the protective effect of these soluble fibers.
- additional proposed mechanisms which would result in cellulose derivatives showing this benefit. These include, but are not limited to, dilution of carcinogens in the GI tract, and decreasing residence time of carcinogens in the GI tract (either by speeding transit of carcinogens or by elimination of pro- carcinogens prior to their conversion to carcinogens). Both the dilution and faster transit effects are caused by the ability of the fibers to resist degradation and hold water.
- the gut contents are made both bulkier and softer through this action, and the propulsive motility of the gut is more effective with softer material. Therefore, the water-soluble cellulose derivatives (e.g., methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose) would show a benefit in reducing the incidence of colon cancers.
- the present invention has found, unexpectently that the combination of psyllium plus wheat bran was less effect than wheat bran alone or in combination with a water soluble cellulose derivative, such as methylcellulose.
- This combination of methylcellulose and wheat bran is more effective that the widely accepted protective fiber, and better than the previously published combination therapy.
- the present invention as shown below, also supports the proposition that enhanced protection is obtained by use of methylcellulose alone.
- Standard animal models may be employed to demonstrate the protective effect of cellulose derivatives against colon and other cancers.
- Experimental and epidemiological evidence suggest that increased dietary fiber is associated with decreased breast cancer risk. Little is known about the role played by different types of fiber and, particularly, mixtures of soluble and insoluble fibers similar to those consumed by human populations in reducing breast cancer risk.
- High intake of fiber may suppress bacterial hydrolysis of biliary estrogen conjugates to free (absorbable) estrogens in the colon and thus may decrease the availability of circulating estrogens necessary for the development and growth of breast cancers.
- Example 1 An example of one such published colon tumor study as applied to psyllium and wheat bran is shown below. Using this model, but with methylcellulose, alone or in combination with wheat bran is proposed. The primary measure to demonstrate the benefit thereof would be the number of preneoplastic aberrant crypt foci.
- the rats are fed the experimental diets for 2 weeks, and then are given two subcutaneous, injections of AOM (15 mg/kg body wt./week). Twenty-three weeks following the first injection of AOM, the incidence of colon tumors in the different dietary groups (12 rats/group) is compared.
- diets that include wheat bran in combination with a water soluble cellulose derivative could be an effective means of reducing colon cancer risk in human populations addicted to high risk western diets.
- Example 2 The protective benefit in breast cancer of water soluble fibers could be demonstrated with a study design such as the following.
- the primary efficacy measures would be total tumor number and multiplicity of mammary adenocarcinomas.
- One hundred fifty virgin female F344 rats are fed the NIH-07 diet from 28 days of age until 50 days of age; they are then given a single dose (40 mg/kg of body weight) of MNU by tail vein injection. Three days later, they are randomly assigned to one of five experimental dietary groups (30 animals per group). Soft, white wheat bran (45% dietary fiber content) and water soluble cellulose is added to a modified (high-fat) American Institute of Nutrition (ATN)-76A diet at the following percents, respectively: 12% + 0% (group 1), 8% + 2% (group 2), 6% + 3% (group 3), 4% + 4% (group 4), and 0% + 6% (group 5).
- ATN American Institute of Nutrition
- Blood, urine, and feces are collected and analyzed by radioimmunoassay techniques for estrogens. Cecal contents are analyzed for bacterial beta-D-glucuronidase activity. After 19 weeks on the experimental diets, the rats are killed, and mammary tumors are counted and classified by histologic type. Cumulative tumor incidence is evaluated by the Kaplan-Meier life-table method and the logrank test. Tumor number is evaluated by the chi-squared test of association, and tumor multiplicity is evaluated by the Mantel- Haenszel chi-squared test. All statistical tests are two-tailed. The experiment was undertaken with the belief that the addition of an insoluble (wheat bran) fiber and a water soluble cellulose derivative to a high-fat would provide a tumor-inhibiting effect in this mammary tumor model.
- psyllium a partially fermentable viscous fiber
- MC methylcellulose
- WB wheat bran
- Rats were injected with azoxymethane, 15 mg/kg s.c, on weeks 5 and 6. Rats were killed by CO2 inhalation, and colon, liver, and blood samples were obtained. ACFs were quantitated from methylene blue stained, formalin fixed sections by a blinded observer.
- a water-soluble non-fermentable cellulose derivative as a dietary component, it will normally be used as is, or they may be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
- the cellulose derivatives may conveniently be administered orally, in a number of ways. They may be administered in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the final desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of "active ingredient" with which it is to be combined, the route of administration and other well-known variables.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the pharmaceutical carrier employed may be, for example, either a solid or liquid.
- solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- liquid carriers are syrup, peanut oil, olive oil, water and the like.
- the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
- the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, or nonaqueous liquid suspension.
- An effective oral dosage regimen in a human would range from about 0.4 to about 30 grams per day, preferably from about 0.5 to about 20 gram/day, more preferably from about 1.0 grams to about 10 grams/day. Preferably, the minimum intake is greater than 2-3 grams/day.
- the dry weight of a typical of an adult human diet is about 500 g/day, and should include at least about 25-30 g of fiber.
- a healthy human diet should contain at least about 5-6% fiber by weight.
- a typical U.S. diet contains about half this level.
- the present invention while making up the fiber intake deficit present in the current human diet with water soluble cellulose derivative will help to reduce cancer risk. It is recognized that while cellulose derivatives may also be protective when added to diets with recommended levels of fiber, the benefit would will most likely be most notable in people who habitually eat less fiber than they should.
- the optimal quantity and spacing of individual dosages will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses given per day can be ascertained by those skilled in the art.
- a suitable, alternative formulation for use herein includes, but is not limited to the fast dissolving methylcellulose tablets as described in Daggy et al., PCT/US98/17405, filed 8/21/98, or PCT/US98/17440, filed 8/21/98, whose disclosures are incorporated herein by reference in their entirety. All publications, including but not limited to patents and patent ' applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7237098P | 1998-01-23 | 1998-01-23 | |
US72370P | 1998-01-23 | ||
PCT/US1999/001377 WO1999037311A1 (en) | 1998-01-23 | 1999-01-21 | Cellulose derivatives and colorectal cancer risk reduction |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1047433A1 true EP1047433A1 (en) | 2000-11-02 |
EP1047433A4 EP1047433A4 (en) | 2009-04-29 |
Family
ID=22107134
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99903303A Withdrawn EP1047433A4 (en) | 1998-01-23 | 1999-01-21 | Cellulose derivatives and colorectal cancer risk reduction |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1047433A4 (en) |
JP (1) | JP2002501029A (en) |
CA (1) | CA2317744A1 (en) |
WO (1) | WO1999037311A1 (en) |
ZA (1) | ZA99478B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2666606A1 (en) * | 2006-10-20 | 2008-05-02 | Dow Global Technologies Inc. | Preventing or reducing oxidative stress or oxidative cell injury by the administration of a water-insoluble cellulose derivative |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03151854A (en) * | 1989-11-10 | 1991-06-28 | Calpis Food Ind Co Ltd:The | Composition for improving intestinal environment |
WO1995013801A1 (en) * | 1993-11-17 | 1995-05-26 | Commonwealth Scientific And Industrial Research Organisation | Fatty acid delivery system |
WO1999001149A1 (en) * | 1997-06-30 | 1999-01-14 | Sigma Pharmaceuticals Pty. Ltd. | Health supplement |
-
1999
- 1999-01-21 WO PCT/US1999/001377 patent/WO1999037311A1/en active Application Filing
- 1999-01-21 EP EP99903303A patent/EP1047433A4/en not_active Withdrawn
- 1999-01-21 CA CA002317744A patent/CA2317744A1/en not_active Abandoned
- 1999-01-21 JP JP2000528293A patent/JP2002501029A/en active Pending
- 1999-01-22 ZA ZA99478A patent/ZA99478B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03151854A (en) * | 1989-11-10 | 1991-06-28 | Calpis Food Ind Co Ltd:The | Composition for improving intestinal environment |
WO1995013801A1 (en) * | 1993-11-17 | 1995-05-26 | Commonwealth Scientific And Industrial Research Organisation | Fatty acid delivery system |
WO1999001149A1 (en) * | 1997-06-30 | 1999-01-14 | Sigma Pharmaceuticals Pty. Ltd. | Health supplement |
Non-Patent Citations (5)
Title |
---|
ALABASTER O ET AL: "DIETARY FIBER AND THE CHEMOPREVENTIVE MODELATION OF COLON CARCINOGENESIS" MUTATION RESEARCH, AMSTERDAM, NL, vol. 350, 1 January 1996 (1996-01-01), pages 185-197, XP002920676 ISSN: 0027-5107 * |
ALABASTER O ET AL: "POTENTIAL SYNERGISM BETWEEN WHEAT BRAN AND PSYLLIUM: ENHANCED INHIBITION OF COLON CANCER" CANCER LETTERS, NEW YORK, NY, US, vol. 75, 1 January 1993 (1993-01-01), pages 53-58, XP002920675 ISSN: 0304-3835 * |
COHEN L A ET AL: "WHEAT BRAN AND PSYLLIUM DIETS: EFFECTS ON N-METHYLNITROSOURA-INDUCED MAMMARY TUMORGENESIS IN F344 RATS" JOURNAL OF THE NATIONAL CANCER INSTITUTE, OXFORD UNIVERSITY PRESS, GB, vol. 88, no. 13, 3 July 1996 (1996-07-03), pages 899-907, XP002920677 ISSN: 0027-8874 * |
FOLINO M ET AL: "Dietary fibers differ in their effects on large bowel epithelial proliferation and fecal fermentation-dependent events in rats" JOURNAL OF NUTRITION, WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, PHILADELPHIA, PA, US, vol. 125, no. 6, 1 January 1995 (1995-01-01), pages 1521-1528, XP009018240 ISSN: 0022-3166 * |
See also references of WO9937311A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP1047433A4 (en) | 2009-04-29 |
ZA99478B (en) | 1999-07-23 |
WO1999037311A1 (en) | 1999-07-29 |
JP2002501029A (en) | 2002-01-15 |
CA2317744A1 (en) | 1999-07-29 |
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