Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-03-08
1998-07-21
Chambers, Jasemine C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
800 2, 800DIG1, 514 44, 4351723, C07H 2104, C12N 1500
Patent
active
057836817
DESCRIPTION:
BRIEF SUMMARY
CONTINUING DATA
This application is a national stage application of PCT/CA93/00319, filed Aug. 9, 1993 and claims priority under 35 USC 119 to GB 9216851.7, filed Aug. 7, 1992.
FIELD OF THE INVENTION
The present invention is concerned with a novel DNA molecule and fragments thereof, which permits production of an (1) assay for androgenic or anti-androgenic materials, (2) transgenic non-human eukaryotic animals models for prostatic disease, (3) cell culture models for prostatic disease, and (4) treatment of human benign prostatic hyperplasia and human prostate cancer by gene therapy. This invention permits assays on agonist and antagonist of the androgen receptor or pathways that result in androgen action, testing materials for carcinogenicity on the prostate, testing drugs and gene therapy, or protection potential of materials on prostatic cells against prostatic disease.
BACKGROUND OF THE INVENTION
A clinical need to assay the function of the androgen receptor (AR) occurs when defects appear in the pathway of androgen action. For example, mutations in the AR affect the bioactivity of the receptor in Androgen Insensitivity Syndrome, AIS, (Kazemi-Esfarjani et al., 1993; Brinkmann et al., 1991; Brinkmann et al., 1992a; Brinkmann et al., 1992b; De Bellis et al., 1992; French et al., 1990; Imperato-McGinley et al., 1990; Lubahn et al., 1989; Quigley et al., 1992; Ris-Stalpers et al., 1990; Ris-Stalpers et al., 1991; Simental et al., 1992) or testicular feminized animals (Yarbrough et al., 1990; He et al., 1991), Kennedy Syndrome (La Spada et al., 1991), prostate cancer (Newmark et al., 1992; Brinkmann et al., 1991; Veldscholte et al., 1992b; Veldscholte et al., 1992a; Veldscholte et al., 1990) and breast cancer (Wooster et al., 1992). Besides mutations directly in the receptor, defects can occur in the non-androgenic mechanism for steroid receptor activation as has been reported for steroid receptors (Power et al., 1991; Shemshedini et al., 1992; Kuiper et al., 1993). An assay that would measure the extent of these defects would also provide a tool to test new materials that may activate the defective receptor and form the basis of a therapy.
Androgen receptors are members of a nuclear receptor superfamily which are believed to function primarily as transcription factors that regulate gene activity through binding specific DNA sequences to hormone responsive elements (HRE) and associated factors (Allan et al., 1991; Smith et al., 1993; Evans, 1988; Beato, 1989). In general, these HREs can be grouped into two categories of inverted repeat consensus sequences: the TGACC motif that mediates estrogen, retinoic acid, and thyroid hormone responses (Klein-Hitpass et al., 1986; Umesono et al., 1988); and the TGTTCT sequence that confers regulation by glucocorticoids, progestins and androgens (Scheidereit et al., 1986; Shrahle et al., 1987; Ham et al., 1988). The inclusion of the androgen receptor responsive element (ARE) in this latter group is based largely on observed binding of androgen receptors to the glucocorticoid responsive element (GRE) of mouse mammary tumor virus (MMTV) DNA (Ham et al., 1988; Roche et al., 1992; Darbre et al., 1986; Cato et al., 1987) and the tyrosine aminotransferase (TAT) gene (Denison et al., 1989).
Androgen regulation of the C3(1) gene which encodes a polypeptide component of prostatic steroid-binding protein has been investigated (Heyns et al., 1978; Hurst et al., 1983; Parker et al., 1988; Parker et al., 1980). Although sequences within both the promoter region and first intron of the C3(1) gene have high affinity binding for androgen receptors (Perry et al., 1985; Claessens et al., 1993; De Vos et al., 1991; Rushmere et al., 1990), attempts to use these sequences to confer androgen regulation on a homologous or heterologous promoter-reporter system have met with limited success (Parker et al., 1985; Parker et al., 1988); with only a weak androgen induction seen with these genomic fragments (Claessens et al., 1993; Tan et al., 1992; De Vos et al., 1991; Rushmere et al., 1990; C
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Chambers Jasemine C.
Clark Deborah J. R.
University of Manitoba
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