Biomedical subjects

B Chatterjee

Publications and source records attributed to B Chatterjee.

At least 37 records · Page 2Linked to original sources

PubMed1999

The immunological and clinical effects of immunotherapy in patients suffering from house dust allergy.

A group of 48 patients with asthma and rhinitis, sensitive to house dust allergen, underwent immunotherapy with an extract of crude house dust for a period of 6-12 months. The clinical results of the therapy, as evaluated by symptom medication scores, demonstrated the significant clinical improvement of the patients treated by crude dust extract (CDE) compared to those treated by placebo. A significant (p < 0.001) reduction of specific IgE and elevation (p < 0.001) of specific IgG in the post-therapeutic patient sera was demonstrated by serological tests. A good correlation was observed between the changes in specific IgE and IgG levels.

Adolescent↗

PubMed1998

Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter.

Dehydroepiandrosterone sulfotransferase (Std) catalyzes sulfonation of androgenic steroids and certain aromatic procarcinogens. In rats, this enzyme is selectively expressed in the liver, and its expression is strongly repressed by androgens. DNase I footprinting and electrophoretic mobility shift analyses revealed two hepatocyte nuclear factor-1 (HNF1), three CCAAT/enhancer-binding protein (C/EBP), and one consensus palindromic thyroid hormone response elements within the first 215 base pairs (bp) of the promoter sequence of rat Std. This promoter is normally inactive in fibroblast-derived NIH 3T3 cells. However, overexpression of HNF1 and C/EBP resulted in synergistic activation of the Std promoter in this cell type, indicating essential roles of these two trans-regulators in liver-selective expression of the rat Std gene. On the other hand, point mutations at any one of five cis elements proximal to the -215 bp region markedly reduced reporter gene expression, suggesting that all of these sites are important for overall promoter function. Androgenic repression of the Std gene in rat liver can be recapitulated in androgen receptor (AR)-negative HepG2 hepatoma cells after cotransfection with an AR expression plasmid. Functional assay of a nested set of 5'-deleted promoters mapped the negative androgen response region between positions -235 and -310. Antibody supershift and oligonucleotide competition identified three OCT-1 and two C/EBP elements between bp -231 and -292. An additional OCT-1 site was found to overlap with a C/EBP element at the -262/-252 position. Mutational inactivation of any one of five cis elements within the -231/-292 region abolished negative androgen response. However, none of these cis elements showed DNase I protection by recombinant AR in footprinting assay, suggesting the absence of a direct AR-DNA interaction. Thus, these studies on rat Std promoter function indicate that (i) HNF1 and C/EBP are responsible for liver specificity of the rat Std gene; (ii) androgenic repression of the gene requires the presence of all of the OCT-1 and C/EBP elements between positions -231 and -292; and (iii) AR may exert its negative regulatory effect indirectly through transcriptional interference of OCT-1 and C/EBP rather than through a direct DNA-AR interaction.

3T3 Cells↗

PubMed1998

Inhibition of androgen action by dehydroepiandrosterone sulfotransferase transfected in PC-3 prostate cancer cells.

Age-dependent loss of androgen sensitivity of the rat liver is associated with a marked increase in dehydroepiandrosterone/hydroxysteroid sulfotransferase (rStd) activity. Sulfonated steroid hormones are known to be ineffective in binding receptor proteins. These observations suggest that intracellular androgen sulfonation can physiologically influence androgen action. We have examined the inhibitory effect of rStd on androgen action in the human prostate cancer-derived PC-3 cells transfected with the rat androgen receptor (AR) expression plasmid and two androgen-responsive promoter reporter constructs (murine mammary tumor long-terminal repeat ligated to chloramphenicol acetyltransferase (CAT) gene and rat probasin androgen response element (ARE) ligated to firefly luciferase (LUC) gene). These transfected cells were dependent on 5alpha-dihydrotestosterone (DHT) for the activation of both reporter genes and showed about a 200- and a 800-fold increase of CAT and LUC activity, respectively, at 10(-10) M DHT over the no-hormone control. Expression of the sulfonating enzyme in this cell transfection system via the rStd expression plasmid caused a dose-dependent decline in the reporter activity with approximately 90% inhibition of androgen action at a rStd:AR plasmid ratio of 100. From these results we conclude that irrespective of a high level of AR, changes in the Std expression can markedly alter the androgen sensitivity of target cells.

Adenocarcinoma↗

PubMed1998

Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern.

The homozygous mouse mutant aphakia (ak) has been characterized by bilaterally aphakic eyes without a pupil [Varnum DS, Stevens, LC (1968): J Hered 59:147-150]. The mutation was mapped to chromosome 19 [Varnum DS, Stevens, LC (1975): Mouse News Lett 53:35]. Our linkage studies yielded a precise localization of the ak gene 0.6 +/- 0.3 cM proximal to the microsatellite marker D19Mit10 and 0.7 +/- 0.4 cM distal to D19Mit4 and D19Mit91. No recombination was found with the marker D19Mit9 among 418 backcross offspring tested. The developmental control gene Pax2 mapped 11.0 +/- 3.5 cM proximal to ak and is excluded as a candidate gene. Sequence analysis of Fgf8 and Chuk1, which are localized close to the marker D19Mit10, detected no mutations in the ak/ak mutants. Histological analysis of homozygous mutants suggested the arrest of lens development at the lens stalk stage, a transient morphological structure during the formation of the lens vesicle. In the lens remnants, Pax6 and Six3 are expressed, whereas in the persisting lens stalk only Pax6 was detected. The expression pattern of Pax2 appeared normal; Cryaa expression could not be detected. As a consequence of the arrested lens development, other ocular tissues that require for their development information from the intact lens, such as iris, ciliary muscle, retina, and vitreous body, are absent or formed abnormally.

Animals↗

PubMed1998

Molecular, genetic and biochemical characterization of lactate dehydrogenase-A enzyme activity mutations in Mus musculus.

Four independent heterozygous lactate dehydrogenase (LDH) mutations with approximately 60% of wild-type enzyme activity in whole blood have been recovered. The mutant line Ldh1a2Neu proved to be homozygous lethal, whereas for the three lines Ldh1a7Neu, Ldh1a11Neu, and Ldh1a12Neu homozygous mutants with about 20% residual activity occurred in the progeny of heterozygous inter se matings. However, the number of homozygous mutants was less than expected, suggesting an increased lethality of these animals. Various physicochemical and kinetic properties of LDH are altered. Exons of the Ldh1 gene were PCR amplified and sequenced to determine the molecular lesion in the mutant alleles. Ldh1a2Neu carried an A/T-->G/C transition in codon 112 (in exon 3), resulting in an Asn-->Asp substitution; Asn112 is part of the helix alpha D, which is involved in the coenzyme-binding domain. Ldh1a7Neu contained an A/T-->C/G transversion within the codon for residue 194 in exon 4, causing an Asp-->Ala substitution, which may affect the arrangement of the substrate-binding site. Three base substituions were discovered for the mutation Ldh1a11Neu in exon 7: the transition C/G-->T/A, a silent mutation, and two transversions C/G-->A/T and C/G-->G/C, both missense mutations, which led to the amino acid replacements A1a319-->Glu and Thr321-->Ser, respectively, located in the alpha H helix structure of the COOH tail of LDHA. We suggest that the mutation in the result of a gene conversion event between Ldh1a wild-type gene and the pseudogene Ldhl-ps. The alteration Ile-->Thr of codon 241 in exon 6 caused by the base pair change T/A-->C/G was identified in the mutation Ldh1a12Neu; Ile241 is included in the helix alpha 2G, a structure that is indirectly involved in coenzyme binding. Each of the sequence alterations has a potential impact on the structure of the LDHA protein, which is consistent with the decreased LDH activity and biochemical and physiological alterations.

Amino Acid Sequence↗

PubMed1998

A rapid and reliable PCR-based assay for gene transmission and sex determination in newborn transgenic mice.

This article describes a reliable and rapid method for simultaneous detection of a transgene and sex determination in the newborn mouse pups by PCR using three sets of primers in a single reaction. One set of sense/antisense primers is used to amplify the experimental transgene (androgen receptor gene in this case), the second set for the mouse Y-chromosome-specific SRY gene, and the third set for the beta subunit of the thyroid stimulating hormone (TSH beta), an internal control. This procedure allowed us to promptly analyze pups born from transgenic founders carrying the androgen receptor transgene and, at the same time, establish the sex of the animals. The method is simple, rapid and highly reproducible.

Animals↗

PubMed1998

Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme.

Androgen receptor (AR) plays a key role in cell growth both in the normal prostate and in prostate cancer. Androgen ablation and prolonged antiandrogen therapy can give rise to AR-dependent prostate tumors, which nonetheless can grow in the androgen-deprived milieu. Here we describe the ribozyme approach to selectively degrading the AR mRNA and thereby inhibiting AR function. A trans-acting hammerhead ribozyme was designed to cleave the rat AR mRNA at the position +1827/ 1828, a region predicted to be minimally involved in generating stable secondary structures. Using AR mRNA fragments as substrates, it was established that this ribozyme can specifically cleave the RNA target in a sequence-specific manner. Kinetic experiments determined a Km for the substrate of 77 nM and a kcat/Km value of 1.8 x 10(7) M(-1) x min(-1), suggesting a catalytic efficiency similar to that of protein enzymes such as the relatively nonspecific ribonuclease A and a sequence-specific endonuclease EcoRI. Transient cotransfections of prostate-derived PC3 cells with three plasmids, an AR-inducible chloramphenicol acetyltransferase (CAT) reporter, an AR expression vector, and a ribozyme expression vector, showed that the ribozyme was capable of reducing the functional activity of AR. At an equimolar ratio of the AR expression plasmid to ribozyme expression plasmid, androgen-inducible CAT activity was inhibited 70%. Similar extents of inhibition were also observed at the cellular mRNA level using ribonuclease protection assays, indicating that the ribozyme functioned as an AR mRNA cleaving enzyme in cellulo. Immunocytochemical examination revealed a decline of AR immunoreactivity in ribozyme-transfected cells. In addition, no morphologically detectable cellular abnormalities were associated with ribozyme expression, indicating the absence of deleterious side effects. These results offer a new avenue for the control of AR function and cell growth, especially in the case of androgen-resistant, but AR-dependent, prostate cancer cells.

Animals↗

PubMed1997

Structure of active chromatin: isolation and characterization of transcriptionally active chromatin from rat liver.

Rat liver nuclei were isolated in low-ionic-strength buffer in the absence of bi- and multi-valent cations. Digestion of these nuclei by endogenous nuclease, micrococcal nuclease and DNase I revealed that a minor chromatin fraction was preferentially digested into poly- and oligo-nucleosomes. Southern blot hybridization with various active gene probes confirmed that these chromatin fragments represent coding and 5' upstream regions of transcriptionally active chromatin. Active chromatin fragments were released selectively into the medium, with inactive chromatin remaining inside the nuclei, under the above ionic conditions. The inclusion of bivalent cations during the digestion of nuclei reversed the solubility behaviour of active chromatin. Rearrangement and exchange of histone H1 between chromatin fragments was prevented by using low-salt conditions in all steps in the absence of bivalent cations. All histones, including H1, were present in stoichiometric amounts in this active chromatin fraction. Active nucleosomes showed a lower electrophoretic mobility than bulk nucleosomes in an acrylamide/agarose composite gel in the absence of Mg2+, but were selectively bound to the gel in the presence of this ion.

Animals↗

PubMed1997

Further biochemical and biophysical characterisation of scyllin, Scylla serrata hemolymph lectin.

The amino acid and carbohydrate analysis of scyllin, a low molecular weight lectin purified from Scylla serrata (edible crab) haemolymph reveal that scyllin is rich in acidic and neutral amino acids and contains high amount of mannose. UV absorption of scyllin is perturbed by DMSO at 272 nm showing the presence of tryptophan molecule in scyllin exposed and accessible to the solvent. The oxidation of tryptophan molecule by N-bromosuccinimide results in loss of haemagglutinating activity of lectin. The study of thermodynamic parameters of scyllin-glycoproteins interaction suggests that ceruloplasmin is the most potent inhibitors of scyllin of all the glycoproteins studied.

Amino Acids↗

PubMed1997

Functional role of a conformationally flexible homopurine/homopyrimidine domain of the androgen receptor gene promoter interacting with Sp1 and a pyrimidine single strand DNA-binding protein.

The androgen receptor (AR) gene promoter does not contain the TATA or CAAT box, but it contains a long (approximately 90-bp) homopurine/homopyrimidine (pur/ pyr) stretch immediately upstream of the Sp1-binding GC box site. This pur-pyr stretch is conserved at the same proximal position in the rat, mouse, and human AR gene promoters. Mutation of this region results in a 3-fold decline in promoter activity, indicating an important regulatory function. Examination of the conformational state of the AR pur/pyr region with the single-strand-specific S1 nuclease showed that it is capable of forming a non-B DNA structure involving unpaired single strands. Fine mapping of the S1-sensitive site revealed an unsymmetric cleavage pattern indicative of an intramolecular triple helical H-form DNA conformation. Electrophoretic mobility shift analyses showed that the pur/pyr region of the AR promoter can bind a novel pyrimidine single-strand-specific protein (ssPyrBF) and also a double-strand DNA-binding protein. Both oligonucleotide cross-competition and antibody supershift experiments established that the double-strand binding protein is equivalent to Sp1. Deoxyribonuclease I (DNase I) footprinting analysis showed multiple Sp1-binding to the pur/pyr site and a weaker Sp1 interaction to this region compared with the adjacently located GC box, where Sp1 functions to recruit the TFIID complex. These results suggest that the pur/pyr domain of the AR gene can serve to attract additional Sp1 molecules when it exists in the double-stranded B-DNA conformation. However, binding of ssPyrBF and the resultant stabilization of the non-B DNA structure is expected to prevent its interaction with Sp1. We speculate that in the TATA-less AR gene promoter, multiple weak Sp1 sites at the pur/pyr region adjacent to the GC box can provide a readily available source of this transcription factor to the functional GC box, thereby facilitating the assembly of the initiation complex.

Animals↗

PubMed1996

The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney.

We describe a new mouse frameshift mutation (Pax2(1Neu)) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183-2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the mid-hindbrain region, loss of Pax2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.

Abnormalities, Multiple↗

PubMed1996

Sequence analysis of the beta B2-crystallin cDNA of hamster containing a domain conserved among vertebrates.

The cDNA sequence of the beta B2-cry was determined from hamster (Mesocricetus auratus) and compared to the corresponding genes of bovine, frog, chicken, human, mouse and rat. Multispecies comparison demonstrated high homology between the hamster, rat and mouse gene, but larger distances to man, bovine, chicken and frog. There is striking identity within a strech of 36 deduced amino acids (aa) between the Greek key motif 3 and part of motif 4. This 36-aa domain contains a putative phosphorylation site for protein kinase C and is highly conserved among all known basic beta B-Cry; however, it can neither be detected in the acidic beta A-nor in the gamma-Cry.

Amino Acid Sequence↗

PubMed1996

Targeted overexpression of androgen receptor with a liver-specific promoter in transgenic mice.

The rodent liver displays marked age- and sex-dependent changes in androgen sensitivity due to the sexually dimorphic and temporally programmed expression of the androgen receptor (AR) gene. We have altered this normal phenotype by constitutive overexpression of the rat AR transgene in the mouse liver by targeting it via the human phenylalanine hydroxylase (hPAH) gene promoter. These transgenic animals in their heterozygous state produce an approximately 30-fold higher level of the AR in the liver as compared with the nontransgenic control. Androgen inactivation via sulfonation of the hormone by dehydroepiandrosterone sulfotransferase (DST), an androgen-repressible enzyme, also contributes to the age- and sex-dependent regulation of hepatic androgen sensitivity. DST has a broad range of substrate specificity and is responsible for the age- and sex-specific activation of certain polycyclic aromatic hepatocarcinogens as well, by converting them to electrophilic sulfonated derivatives. In the transgenic female, the hepatic expression of DST was approximately 4-fold lower than in normal females, a level comparable to that in normal males. The hPAH-AR mice will serve as a valuable model for studying the sex- and age-invariant expression of liver-specific genes, particularly those involved in the activation of environmental hepatocarcinogens such as the aromatic hydrocarbons.

Animals↗

PubMed1996

Age-dependent expression of the androgen receptor gene in the prostate and its implication in glandular differentiation and hyperplasia.

The senescence phenotype is the product of both cumulative physical damages during the life span and a species-specific genetic program. The genetic program of aging appears to have co-evolved with the sexual mode of reproduction. The same developmental processes that prepare the animal for maximum vitality and reproductive competence during young adulthood, if allowed to continue, can be detrimental during old age. Androgen receptor-mediated development and growth of the prostate gland is an example of such "antagonistic pleiotropy." The prostate gland is composed of two major groups of cells: the epithelial and stromal. Among the epithelial type, the columnar cells on the luminal surface produce the prostatic secretions, and the basal cells are presumed to serve as progenitors of the columnar cells. Within the stromal cell population, fibroblastic and smooth muscle cells are thought to produce growth factors that support the development and function of the epithelial cells. Both epithelial and stromal cells are dependent on androgens. In this study, we have examined age-dependent expression of the androgen receptor gene in the prostatic tissues of rats and dogs. Unlike the rat, in which the prostatic growth ceases after sexual maturation, the dog prostate continues to grow during aging. Similar to the dog, the antagonistic pleiotropy of the prostatic growth in the human causes the pathological condition of benign prostatic hyperplasia (BPH), the major health problem in old men. Quantitation of the androgen receptor (AR) mRNA in the total prostate extracts from young and old animals by the reverse transcriptase-polymerase chain reaction (RT-PCR) method showed about a 30% decline in AR mRNA in the 24-month-old rat prostate, as compared to the prostate of 3-month-old young adult animals. However, no significant difference in AR mRNA contents between 1-year-old and 10-year-old dog prostates was observed. In situ immunostaining for the androgen receptor protein revealed that in the case of rat, developmental maturation during the first month of life is associated with an increase in AR immunoreactivity in the luminal columnar epithelium, with a concomitant loss of immunoreactivity in the basal cells. Furthermore, with aging, there was a marked increase in the proportion of AR-negative basal cells in comparison to luminal columnar cells. Surprisingly, in both young adult (approximately 1-year-old) and old (approximately 10-year-old) dogs, most of the AR immunoreactivity was localized in the fibroblastic stromal cells rather than in the epithelial cells. Based on these observations and the existing literature, we propose that normally, in most mammalian species, an age-dependent decline in the conversion of basal to columnar epithelial cells after sexual maturation serves as a stop signal for the prostate growth. However, in certain species, such as the dog, robust AR expression in the stromal cells overrides this regulatory blockage and leads to prostatic hyperplasia in old age.

Aging↗

PubMed1996

Diversity of rotavirus strains infecting pediatric patients in New Delhi, India.

Polyacrylamide Gel Electrophoresis (PAGE) of rotavirus can provide information on variation in rotavirus strain prevalent in the community. In the present study 157 samples were collected from children below 5 years of age presenting with acute diarrhoea from May to December, 1990 at Safdarjung Hospital, New Delhi. Seventy-one (45 percent) of these stool samples were positive for rotavirus by ELISA. Sixty-seven samples showed discernible RNA pattern of group A rotavirus by PAGE. It was found that there were seven electropherotypes co-circulating in this 8-month period. Majority of the strains had a IIC pattern, but IIA, IID, IIE, IIG, IE, and IB electropherotype patterns were also seen. The simultaneous co-circulation of multiple group A strains in the community may lead to extensive genomic variation in rotavirus strains.

Acute Disease↗

PubMed1996

HPV 16 DNA sequences in different grades of cervical lesions.

A simple rapid method for isolation of genomic DNA from cervical scrape cells has been standardized. Sufficient amount of good quality genomic DNA was isolated from each cervical scrape specimen. Total 120 cervical scrape specimens from wide spectrum of cervical lesions were analysed for the presence of HPV 16 DNA by Southern hybridization using 32P labelled HPV 16 DNA as probe under stringent conditions. Viral DNA sequences were detected in 78 of the specimens. About 36% (5 out of 14) of normal cervical smears and 59% (46 out of 78) of inflammatory cervical smears had the viral DNA sequences. Except a lone sample, the rest 27 samples of different grades of dysplasia specimens and squamous cell carcinoma samples had viral DNA sequences. Due to development of sensitive Southern hybridization method, the presence of HPV 16 DNA could be detected in high percentage of specimens belonging to the inflammatory cervical specimens.

DNA, Viral↗

PubMed1995

Molecular cloning and sequence analysis of the rat liver carnitine octanoyltransferase cDNA, its natural gene and the gene promoter.

The full-length cDNA and the natural gene for rat peroxisomal carnitine octanoyltransferase (COT) have been isolated and sequenced. The 2681 bp long cDNA contains an open reading frame for 613 amino acids, resulting in a protein with a deduced molecular weight of 70,301, and a C-terminal peroxisomal targeting sequence (Ala-His-Leu). The isolated COT cDNA has 51 bp of the 5' untranslated region (UTR), 791 bp of 3' UTR, two putative polyadenylation sites, and a poly(A19-23) tail. Screening of a rat genomic DNA library in the lambda phage with the COT cDNA probe resulted in the isolation of seven overlapping clones, together containing the complete COT gene with seventeen exons. All of the exon-intron boundary sequences conform to the GT-AG rule. The COT gene appears to spread over 40 to 60 kbp region of the rat genome. The transcription initiation site of the COT gene was determined through primer extension, and the promoter sequence up to the position -1140 was established. The promoter lacks the canonical TATA box and a promoter-reporter construct containing the sequence encompassing -1140 to +84 base positions and the firefly luciferase reporter cDNA yielded about 100-fold increase in promoter activity in transfected hepatoma cells. Some of the consensus sequences for putative cis elements present in the promoter sequence are: the two CCAAT motifs for CTF/NF1/CBP binding (at -284 and -93), two GC boxes for Sp1 binding (at -160 and -68), two AP2 sites (at -359 and -25), a half site (TGACCT) for the peroxisome proliferator activated receptor (PPAR) binding at -737 within a partial palindromic sequence region. Potential regulatory elements, such as several palindromes and repeat motifs for five different sequence segments, are also identified.

Amino Acid Sequence↗

PubMed1995

Regulation of androgen action by receptor gene inhibition.

Regulated functions of hormonal agents play a critical role in health and disease. Target cell responsiveness to a hormonal signal is a product of both cellular concentrations of the hormone ligand and the corresponding receptor protein. The major thrust of the drug design for treatment of endocrine-related problems, so far, has been directed to ligand derivatives. In certain cases, receptor regulation through antigene technology has much to offer with improvements in both target cell and hormonal specificity. Three different antigene approaches are currently being explored. The first approach is to inhibit the expression of the receptor gene by disrupting the DNA protein interaction at critical cis-elements by short triple helix-forming oligonucleotides. The second approach is to sequester and inactivate the receptor mRNA by the antisense mRNA produced in the target tissue directed by a heterologous tissue-specific promoter. The third approach is the tissue-specific expression of a catalytic ribozyme that binds to the specific receptor mRNA and selectively degrades it before its translation into the protein. In this study, we have characterized the promoter of the rat androgen receptor, and by progressive deletion from its 5' end have identified two critical cis-regulatory elements, one at the -960 to -940 region and the other at the -554 to -574 positions. The former is an activator while the latter is an inhibitor domain. The inhibitory domain is the binding site for the nuclear factor kappa B (NF-kappa B) and more specifically, the p50/p50 homodimer of this transcription factor family. We have also provided correlative data to show that under normal physiological conditions, the NF-kappa B functions as an antiandrogen during the age-dependent desensitization of the liver. In addition to the naturally functioning antiandrogenic influence of NF-kappa B, we have designed an artificial antiandrogenic agent, a triplex-forming oligonucleotide (TFO) directed to the -960/-940 activator domain of the rat androgen receptor gene promoter. This oligonucleotide at a TFO-to-promoter ratio of 500 is able to cause about 60% inhibition of rAR promoter function in transfected COS-1 cells. These results clearly demonstrate the feasibility of the antigene approach for effective inhibition of steroid hormone action.

Androgens↗