MXPA00007194A - Cellulose derivatives and colorectal cancer risk reduction - Google Patents

Abstract

The present invention is a method of reducing the incidence of colorectal cancers in a mammal in need thereof, which method comprises administering to said mammal a water-soluble, non-fermentable cellulose derivative, alone or in combination with an insoluble fiber and/or a soluble fermentable fiber.

Description

DERIVATIVES OF CELLULOSE AND REDUCTION OF THE RISK OF COLORECTAL CANCER FIELD OF THE INVENTION The present invention is directed to the risks associated with colorectal cancers and food components.

BACKGROUND OF THE INVENTION Colorectal cancer is a common and serious medical condition. The incidence of colon cancer is almost the same in men and women; Rectal cancer is somehow more common in men. Epidemiological studies have shown that when populations migrate from low incidence areas (Eastern Europe or Asia) to a higher incidence area (for example the United States), the incidence of colorectal cancer increases to US levels in the following 10 to 15 years. This suggests that dietary factors play an important role in the incidence of colorectal cancer. In fact, several epidemiological studies have tried to relate the nutritional composition to the relative risks of colon cancer. The intake of dietary fat seems to be positively correlated with this risk. Fiber in food also seems to be important, although this does not apply to all types of fiber. Epidemiological studies can produce inconsistent results because you do not have control over all the components of a diet. For example, do high-fiber diets protect because high-fiber foods also tend to be low in fat and high in antioxidants? Despite such difficulties in the interpretation of the data, some health authorities have recommended that the intake of fiber in the diet should be doubled to approximately 25 to 30 g / day. This goal is reflected in the National Academy of Science health goal that suggests individuals consume five or more servings of fruit or six or more servings of bread, cereals and legumes daily. [References to the above: Committee on Diet & Health, Food & Nutrition Board, Commission on Life Sciences, National Research Council. Diet and Health. Implications for Reducing Chronic Disease Risk. National Academy Press, Washington, D.C., 1989; and R. B. Sause. 1995. Health Implications of Dietary Fiber. US Pharmacist, February issue]. Studies in animals with known colon carcinogens have allowed researchers to study the food components under conditions with greater control. These studies have demonstrated the protective effects of some sources of insoluble fiber (eg wheat bran) and some soluble fermentable fibers (eg, psyllium), as well as other food components such as calcium and some vitamins [Alabaster et al, Dietary fiber and the chemoprotectíve modulation of colon carcinogenesis. Mutat Res 1996 Feb 19; 350 (1): 185-197]. Some studies have shown an increased protection from the combination of wheat bran and psyllium in a colon cancer model [Alabaster et al, Cancer Lett 1993 Nov 30; 75 (1): 53-58] and in a model of breast cancer [Cohen et al, J Nati Cancer Inst 1996 Jul 3; 88 (13): 899-907]. However, there is still a need for additional food components for the prophylactic treatment of colorectal cancer.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a method for reducing the incidence of colorectal cancer in mammals in need thereof, which method comprises administering 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 to said mammal.

DETAILED DESCRIPTION OF THE INVENTION The protective effects of water-soluble, non-fermentable cellulose derivatives (eg methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose) to be used as a food component for the reduction of risk of colon cancer do not appear to be the subject of previous studies in this area. These semi-synthetic fibers have been discovered in the food supply for decades, and are considered safe, but the beneficial clinical effects of these fibers have been considered scarcely outside the area of laxation. Some studies have investigated the ability of cellulose derivatives to lower plasma cholesterol or improve glycemic control, but they have not been used in cancer models, except as vehicles to suspend poorly soluble carcinogens. These fibers have properties that are unique in relation to the fibers that occur naturally in food. They are soluble in 100% water (in cold water, they are insoluble in hot water), and are not fermentable. The naturally occurring soluble fibers such as pectin, psyllium and guar gum are fermentable in the human Gl tract essentially, and completely in the case of pectin or guar, and even important level (~ 50%) in the psyllium case. It is hypothesized that fermentation products, particularly short-chain fatty acid butyrates may be responsible for the protective effects of these soluble fibers. However, additional mechanisms have been proposed that would result in cellulose derivatives that show these benefits. This includes, but is not limited to, the dilution of calcinogens in the Gl tract, and the decrease in the residence time of the carcinogens in the Gl treatment (either by accelerating the transit of the carcinogens or by eliminating the pro-carcinogens before of its conversion to carcinogens). Both effects of dilution and faster transit are caused by the ability of the fibers to resist degradation and contain water. The contents of the intestine become more bulky and soft by its action, and the motility of propulsion of the intestine is more effective with a softer material. Therefore, water-soluble cellulose derivatives (eg, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose) will show a benefit in reducing the incidence of cancer in the colon. The present invention has unexpectedly discovered that the combination of psyllium plus wheat bran has a lower effect than wheat bran alone or in combination with a water soluble cellulose derivative, such as methyl cellulose. This combination of methylcellulose and wheat bran is more effective than the protective fiber widely accepted, it is even better than the combination therapy previously published. In addition, the present invention, as demonstrated above, also supports the proposition that improved protection is obtained by the use of methylcellulose alone.

BIOLOGICAL EXPERIMENTS Standard animal models have been used to demonstrate the protective effect of cellulose derivatives against colon cancer and others. Experimental and epidemiological evidence suggests that an increased amount of fiber in the diet is associated with a decreased risk of breast cancer. Little is known about the role played by different types of fiber, and particularly, mixture of soluble and insoluble fibers similar to those consumed by human populations in the reduction of breast cancer. A high fiber intake can suppress bacterial hydrolysis of conjugated bile estrogens to release (absorbable) estrogens in the colon and thus decrease the capacity of circulating estrogens necessary for the growth development of breast cancers.

EXAMPLE 1 Below is an example of one such study published on colon tumors as applied to psyllium and wheat bran. The use of this model is proposed, but with methylcellulose, alone or in combination with wheat bran. The primary measurement to demonstrate the benefit of it will be the number of preneoplastic aberrant crypt foci. Alabaster et al, Cancer Lett 1993 Nov 30; 75 (1): 53-58 Potential synergism between wheat bran and psyllium: enhanced inhibition of colon cancer, the description of which is incorporated by reference to the present completely. Using this model, but modifying it to include methylcellulose instead of psyllium, the following study compares the influence of diets with high levels of fat (20% w / w) that combine low levels of calcium (0.18% w / w) and low levels. (1% w / w), medium (4% w / w), and high (8% w / w) of dietary fiber from wheat bran (WB), with high levels (8% w / w >) of Food fiber of a water soluble cellulose derivative (WS) alone or in various combinations of WB, in the induction of colon tumors in Fischer-344 rats following exposure to azoxymethane (AOM). The rats were fed the experimental diets for 2 weeks and subsequently administered two subcutaneous injections of AOM (15 mg / kg body weight / week). 23 weeks after the first AOM injection, the incidence of colon tumors in the different diet groups was compared (12 rats / groups). In the Alabaster study, the results showed that increasing the fiber concentration of the WB diet from 1 to 8% significantly reduced the number of colon / group tumors. When the influence of 8% fiber on the WB diet in the development of colon tumors was compared with that of (PS) (WB: PS = 0.100), no significant difference was observed. However, combinations WB and PS showed a greater protective effect than WB or PS alone, at comparable levels of dietary fiber. The 50:50 combination of WB and PS showed maximum protection, while the 25:75 and 75:25 combinations produced intermediate effects. None of the diets showed any significant effect on the normal growth of the rats. The results indicate that WB and PS fiber alone, and to a greater degree in combination, may offer protection against colon cancer promoted by diets with high fat and low calcium levels.

Therefore, diets that include wheat bran in combination with a water-soluble cellulose derivative may be an effective means of reducing the risk of colon cancer in human populations afflicted with high-risk Western diets.

EXAMPLE 2 The protective benefit in breast cancer of water soluble fibers can be demonstrated with a study design as indicated below. The primary efficacy measures will be the total number of tumors and the multiplicity of mammary adenocarcinomas. A suitable model for this is the study shown in Cohen et al., J Nati Cancer Inst 1996 Jul 3; 88 (13): 899-907 Wheat bran and psyllium diets: effects on N-methylnitrosourea-induced mammary tumorigenesis in F344 rats; whose description is incorporated by reference to the present completely. The use of this model but using a suitable water soluble fiber is taught herein. This study can evaluate the effect of wheat bran (an insoluble fiber) and a water soluble cellulose (soluble fiber) alone and in combination on a general estrogen state, on the activity of beta-D-glucuronidase (a key enzyme of deconjugation of estrogen that responds to diets) of fecal bacteria, and in the induction of mammary tumors in rats treated with N-methylnitrosourea (MNU).

Methods 150 virgin female F344 rats are fed the NIH-07 diet from 28 days of age to 50 days of age; they are administered a single dose (49 mg / kg body weight) of MNU by tail vein injection. Three days later, they are randomly assigned to one of five experimental feeding groups (30 animals per group). Soft white wheat bran (45% fiber feed) and water soluble cellulose are added to a modified (high fat) diet from the American Institute of Nutrition (AIN) -76A in the following percentages, respectively: 12% + 0% (group 1), 8% + 2% (group 2), 6% + 3% (group 3), 4% + 4% (group 4), and 0% + 6% (group 5). Blood, urine and feces are collected and analyzed by radioimmunoassay techniques to find estrogens. The cecal contents are analyzed to find bacterial beta-D-glucuronidase activity. After 19 weeks of administration of experimental diets, the rats were sacrificed and mammary tumors were counted and classified by histological type. The cumulative tumor incidence was evaluated by the Keplan-Meier life-table method and the logrank test. The number of tumors is assessed by the chi-square association test, and the multiplicity of tumors is assessed by the chi-square Mantel-Haenszel test. All statistical tests are two-tailed. The experiment was conducted believing that the addition of an insoluble fiber (wheat bran) and a water-soluble cellulose derivative to a high-fat diet would provide a tumor-inhibiting effect in this breast tumor model. To further determine the risk reduction of colon cancer by dietary fiber is possible, a comparison of psyllium (PS), a viscous partially fermentable fiber, to methylcellulose was made (MC), a non-fermentable viscous fiber, in combinations with wheat bran (WB), in an animal model of colon cancer.

Methods Fisher 344 male rats were randomly classified into 7 groups of 10 animals each and were fed for 26 weeks on diets containing one of the following fiber sources (8% w / w) on a semipurified feed basis: WB, microcrystalline cellulose (C), MC, WB: PS (1: 1), or WB: MC (1: 3.1: 1, and 3: 1). The rats received an injection of azoxymethane, 15 mg / kg s.c., at week 5 and 6. The rats were sacrificed by inhalation of CO2, and samples of colon, liver and blood were obtained. ACF of fixed sections in formalin stained with methylene blue was quantified by a blind observer.

Results As expected, the inclusion of PS increased the weight of the colon; MC no. The proportion of large ACF vs. small did not vary by the colon segment or diet. The WB diet showed the lowest number of ACF (78 + 7, mean ± SE), similar to C (87 + 8), although the diets WB PS and 3: 1 WB: MC were significantly higher (133 ± 9 and 106). ± 9, resp., P <0.05). MC alone was also significantly higher (119 ± 11) vs. WB, however, the 1: 1 and 1: 3 mixtures of WB and MC were as effective as the WB alone. The three WB combinations with MC produced significantly less ACF of the WB: PS diet.

Conclusions It is hypothesized that fermentation products of soluble fiber, particularly butyrate, are responsible for this protective effect. These results suggest that fermentation alone can not count for the formation of reduced ACF. If the fermentation were important, one would not expect the observed result of the WB: MC diets compared to the WB: PS diet. Although no particular mechanism of action is suggested, the sustained viscosity and / or the ability to contain water may be important properties of a soluble fiber with respect to chemoprotection. Additionally, since the North American diet and that of many other cultures typically contains wheat bran, these results support the claim that a supplement that provides only the soluble cellulose derivative could also be protective.

Formulations To use a non-fermentable water-soluble cellulose derivative as a food component, it will normally be used as it is, or it may be formulated into pharmaceutical compositions in accordance with standard pharmaceutical practice. The cellulose derivatives can conveniently be administered orally in various ways. They can be administered in combination with a second known therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired final preparation. It will be appreciated that the character form of the pharmaceutically acceptable character or solvent is dictated by the amount of "active ingredient" with which it will be combined, the route of administration and other variables. The vehicle (s) must be "acceptable" in the sense of being compatible with other ingredients of the formulation and not damaging the recipient thereof. The pharmaceutical carrier that is used can be, for example, either a solid or a liquid. Some examples of solid carriers are lactose, magnesia, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearates, stearic acid and the like. Some examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent may include delay material already known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be made into a tablet, placed in a capsule of hard gelatin powder or pellet or troche. When using a liquid carrier the preparation is in the form of syrup, emulsion, soft gelatin capsule or non-aqueous liquid suspension. An effective oral dosage regimen in a human will vary from about 0.4 to about 30 grams daily, preferably from about 0.5 to about 20 grams / day, most 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 in a typical adult human diet is approximately 500 g / day and should include at least 25 to 30 g of fiber. A healthy diet for a human must contain at least about 5 to 6% fiber in weight. A typical diet in the U.S. contains about half of this level. The present invention while covering the deficit of fiber intake present in the current human diet with a water soluble cellulose derivative will help reduce the risk of cancer. It is recognized that although cellulose derivatives can also protect when added to diets with recommended levels of fiber, the benefit will be much more noticeable in people who habitually eat a smaller amount of fiber than they should.

One skilled in the art will recognize that the optimum amount and individual dosage separation will be determined by the nature and degree of condition to be treated, the form, route and site of administration, and the particular patient to be treated, and that said optimum points can be determined. by conventional techniques. One skilled in the art will also appreciate that the optimum course of treatment, ie, the number of doses administered per day, can be decided by those skilled in the art. A suitable, alternative formulation for use herein includes, but is not limited to, rapidly dissolving methylcellulose tablets as described in Daggy et al., PCT / US98 / 17405, filed August 21, 1998 or PCT / US98. / 17440, filed on August 21, 1998, the descriptions of which are hereby incorporated by reference in their entirety. All publications, including by not limited to the patents and patent applications cited in this specification are hereby incorporated by reference as if each individual publication may specifically and individually indicate to be incorporated by reference herein as set forth above. The foregoing description fully describes the invention that includes the preferred embodiments thereof. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the examples herein should be construed as merely illustrative and not as limiting the scope of the present invention in any way. The embodiments of the invention in which property or exclusive privileges are claimed is defined below.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a non-fermentable cellulose derivative soluble in water alone or in combination with an insoluble fiber and / or a soluble fermentable fiber, for the preparation of a composition for reducing the incidence of colorectal cancer in mammals.

2. The use as claimed in claim 1, wherein the non-fermentable water-soluble cellulose derivative is a cellulose ether that is methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, or a combination thereof.

3. The use as claimed in claim 1 or 2, wherein the soluble fermentable fiber is psyllium.

4. The use as claimed in claim 1 or 2, wherein the insoluble fiber is wheat bran.

5. The use as claimed in any of claims 1 to 4, wherein the water-soluble, non-fermentable cellulose derivative is methylcellulose or hydroxypropyl-methylcellulose.

6. The use as claimed in claim 2, wherein the cellulose is provided as a powder in volume, a tablet or suspension, optionally containing sugar.

7. - The use as claimed in claim 6, wherein the cellulose is provided in a fast disintegrating tablet.

8. The use as claimed in claim 1, wherein the composition provides a total daily dosage of about 0.4 grams to 30 grams per day to the patient.

9. The use as claimed in claim 8, wherein the composition provides a total daily dosage of about 1 gram to 10 grams per day to the patient.

10. The use of a water-soluble non-fermentable cellulose derivative, alone or in combination with an insoluble fiber and / or a soluble fermentable fiber, for the preparation of a composition for reducing the incidence of breast cancer in a mammal.

11. The use as claimed in claim 10, wherein the non-fermentable water-soluble cellulose derivative is a cellulose ether that is methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, or a combination thereof.

12. The use as claimed in claim 10 or 11, wherein the fermentable fiber is psyllium.

13. The use as claimed in claim 10 or 11, wherein the insoluble fiber is wheat bran.

14. The use as claimed in any of claims 10 to 13, wherein the water-soluble, non-fermentable cellulose derivative is methylcellulose or hydroxypropylmethylcellulose.