Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-17
2001-08-07
LeGuyader, John L. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S449000
Reexamination Certificate
active
06271257
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for decreasing the intracellular, especially nuclear level of &bgr;-catenin in an individual and to a method for the prevention or treatment of a disease or condition in an individual, wherein said disease or condition is related to a mutant APC gene or to an elevated level of intracellular &bgr;-catenin. Furthermore, the invention relates to methods for screening a subject to determine if said subject is a carrier of a mutant APC gene, and to methods for diagnosing an individual's predisposition for a disease or condition in an individual, said disease or condition being related to a mutant APC gene or to an elevated level of intracellular &bgr;-catenin.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional detail with respect the practice, are incorporated by a reference.
Lignans are defined as a class of phenolic compounds possessing a 2,3-dibenzylbutane skeleton. They are formed by coupling of monomeric units called precursors such as cinnamic acid, caffeic, ferulic, coumaric, and gallic acids (Ayres and Loike, 1990). Lignans are widely distributed in plants. They can be found in different parts (roots, leafs, stem, seeds, fruits) but mainly in small amounts. In many sources (seeds, fruits) lignans are found as glycosidic conjugates associated with fiber component of plants. The most common dietary sources of mammalian lignan precursors are unrefined grain products. The highest concentrations in edible plants have been found in flaxseed, followed by unrefined grain products, particularly rye.
Considerable amounts of lignans are also found in coniferous tree. The type of lignans differs in different species and the amounts of lignans vary in different parts of the trees. The typical liguans in heart wood of spruce (
Picea abies
) are hydroxymatairesinol (HMR), &agr;-conidendrin, conidendrinic acid, matairesinol, isolariciresinol, secoisolariciresinol, liovile, picearesinol, lariciresinol and pinoresinol (Ekman 1979). The far most abundant single component of lignans in spruce is HMR, about 60 percent of total lignans, which occurs maninly in unconjugated free form. Lignan concentration in thick root is 2-3 percent. Abundance of lignans occur in the heart wood of branches (5-10 percent) and twists and especially in the knots, where the amount of lignans may be higher than 10 percent (Ekman, 1976 and 1979). These concentrations are about hundred-fold compared to ground flax powder known as lignan-rich material.
The chemical structure of hydroxymatairesinol is represented by the formula
As an experimental evidence for the chemopreventive actions of lignans, supplementation of a high-fat diet with lignan-rich flaxseed flour (5% or 10%) or flaxseed lignans (secoisolariciresinol-diglycoside, SDG) inhibited the development of antiestrogen-sensitive dimethylbenzanthracene (DMBA)-induced breast cancer in the rat (Serraino and Thompson 1991 and 1972; Thompson et al, 1996a and 1996b). They reduced the epithelial cell proliferation, nuclear aberrations, the growth of tumors, and the development of new tumors. High lignan intake may also protect against experimental prostate and colon cancers.
Germline mutations of adenomatous polyopsis coli (APC) gene may lead to Familial Adenomatous Polyposis (FAP) syndrome. In FAP syndrome, the aberrant function of APC-gene is considered to be an important initiation event for the development of sporadic adenomas in animals and in humans (Fearon et al, 1990; Groden et al, 1991; Herter et al, 1999). APC is a tumor suppressor gene located in chromosome 5
q
21. APC mutation is a very early event in the development of FAP. It occurs already before ras mutations (Powell et al, 1992) and is suggested to be, together with other mutations, a risk factor for colorectal cancer. There is no specific treatment for FAP.
The APC-gene encodes a cytoplasmic that can bind to and promote the degradation of &bgr;-catenin, which plays a dual role in the cell. One role is linking the cytoplasmic side of cadherin-mediated cell-cell contacts to the actin cytoskeleton, and the other is the abiltiy to bind members of the Tcf-family of transcription factors and activate mostly unknown target genes. The target genes most likely involve c-myc, cyclin D1, c-jun and fra-1 that are the components of AP-1, uPAR and PPAR&dgr;. Mutations of APC cause aberrant accumulation of &bgr;-catenin, which alter the expression of above-mentioned genes. Currently it is assumed that over-expression of &bgr;-catenin, which is caused by lack of APC gene function, results in abnormal gene transcription, which promotes the development of benign adenomas, polyps and possibly malignant tumors.
An animal model, which resembles to human FAP syndrome, and which is considered to be the best experimental model for human FAP, is the mouse with APC
min
mutation bearing a heterozygous nonsense mutation at codon 850 of the APC gene. The codon 850 is located at the mutation cluster region, which is the most often mutated region of the APC gene in human colon cancer (Peifer & Polakis, 2000). APC
min
mice develop sporadic adenomas in different parts of the gut. The intracellular distribution of &bgr;-catenin in the adenomas is cytoplasmic and nuclear when compared to mainly membraneous distribution in non-mutated mice. Similar &bgr;-catenin distribution is seen in many human cancers and apc-mutation is considered to be the principal cause of the phenomenon.
The results of the present study indicate that levels and distribution &bgr;-catenin can be regulated by HMR. Futher, the number of adenomas in the experimental mouse model can be decreased by HMR. Thus, HMR can be used for the prevention and treatment of FAP and other diseases which are characterized by elevated level of &bgr;-catenin and its nuclear distribution.
SUMMARY OF THE INVENTION
According to one aspect, this invention concerns a method for decreasing the intracellular level of &bgr;-catenin in an individual, comprising administering to said individual an effective amount of hydroxymatairesinol or a geometric isomer or steroisomer thereof.
According to another aspect, the invention concerns a method for the prevention or treatment of a disease or condition in an individual, said disease or condition being related to a mutant APC gene, or to an elevated level of intracellular &bgr;-catenin, said method comprising administering to said individual an effective amount of hydroxymatairesinol or a geometric isomer or stereoisomer thereof.
According to a third aspect, the invention concerns a method for screening a subject to determine if said subject is a carrier of a mutant APC gene, comprising the steps of
providing a biological sample of the subject to be screened; and
providing an assay for detecting in the biological sample the presence of i) the normal APC gene or II) the mutant APC gene.
According to a fourth aspect, the invention concerns a method for diagnosing an individual's predisposition for a disease or condition in an individual, said disease or condition being related to a mutant APC gene, or to an elevated level of intracellular &bgr;-catenin, said method comprising determining whether said individual has a mutant APC gene, according to the screening method mentioned above.
REFERENCES:
patent: 5709998 (1998-01-01), Kinzler et al.
patent: 5998600 (1999-12-01), Barker et al.
patent: WO 92/13103 (1992-08-01), None
Mahmoud et al. Phenolic antioxidants modulate Apc function in vivo:Implications for colon cancer prevention. Proceeding of the American Association for Cancer Research Annual Meeting. vol. 40, pp. 530, Mar. 1999.*
Bras et al. Oxidative stress in familial adenomatous polyposis. European Journal of Cancer Prevention, vol. 8, No. 4, pp. 305-10, Aug. 1999.*
Saarinen et al. Hydroxymatairesinol, a Novel enterolactone precursor with antitumor properties from coniferous tree (picea abies). Nutrition and Cancer col. 36 No. 2. Abstract, Mar. 2000.*
Herter
Epps Janet
Hormos Nutraceutical Oy Ltd.
LeGuyader John L.
Rothwell Figg Ernst & Manbeck p.c.
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