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We study the implant-induced hydrogenated defects responsible for the Smart Cut™ layer transfer of Si (001) films. Different experimental methods are used to quantify the time dependence of the defect evolution and interactions during isothermal annealings. An optical characterization technique was developed for the statistical analysis of the formation and growth of micrometer size microcracks in the buried implanted layer. We show that the formation of molecular hydrogen is dominated by a transient phenomenon related to the rapid dissociation of the hydrogenated point defects. The impact of the H2 formation kinetics on the microcrack evolution is described and the physical mechanisms involved in their growth are identified. A comprehensive picture of the fracture phenomenon in H implanted Si leading to the full layer transfer is proposed and discussed. [ABSTRACT FROM AUTHOR]

The effect of hydrogen implantation on the transport of impurities in silicon is studied. We use secondary ion mass spectrometry measurements to investigate the depth redistribution of oxygen, carbon, and fluorine during low temperature, ≤450 °C, isothermal anneals. Their fast migration toward the projected range region of H implants points to the existence of a strong interaction of the impurities with H-induced defects. Significantly enhanced, as compared to the literature values, diffusivities of the investigated impurities were obtained. The results reveal that hydrogen implantation can be advantageously used for the impurity profile engineering and gettering studies in silicon in the low temperatures annealing regime. [ABSTRACT FROM AUTHOR]

Background:Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.Methods:Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.Results:Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.Conclusions:In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET. [ABSTRACT FROM AUTHOR]

Background:The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ-confined (NOC) disease in patients undergoing radical prostatectomy (RP).Methods:Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP.Results:[-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [-2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with GS8 and lowest in those with GS6.The difference in [-2]proPSA values between GS8 and GS7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP.Conclusions:Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa. [ABSTRACT FROM AUTHOR]

Background:The TMPRSS2-ERG gene fusion resulting in ERG overexpression has been found in around 50% of prostate cancers (PCa) and is a very early event in tumorigenesis. Most studies have reported on selected surgical cohorts with inconsistent results. We hypothesized that ERG gene rearrangements impact tumor development and investigated the frequency of ERG overexpression in the context of clinicopathological tumor characteristics.Methods:ERG overexpression (ERG+ or ERG-) was determined by immunohistochemistry (IHC) in 1039 radical prostatectomy (RP) tumors and association with PSA, D'Amico risk score, histopathology, biochemical recurrence, body mass index and age of PCa cases was analyzed.Results:ERG+ was associated with younger age at diagnosis (P<0.0001), lower serum PSA (P=0.002) and lower prostate volume (PV) (P=0.001). It was most frequent in the youngest age quartile (55 years, 63.9% ERG+) and decreased constantly with increasing age to 40.8% in the oldest age quartile (67 years, P<0.0001). In the PSA range <4 ng ml−1 the frequency of ERG positivity was 60.2% compared with 47.5 and 49.1% in the PSA ranges 4-10 and 10 ng ml−1, respectively. In the first age quartile, ERG+ patients had lower median serum PSA and fPSA% and smaller PV. In the highest age quartile tumor volume (TV) was increased. Similar differences were observed in the low PSA range. Multivariate analysis identified the first age quartile as a predictor for ERG status (odds ratios (OR) 2.05, P=0.007). No association was found with the D'Amico progression risk score and with biochemical tumor recurrence.Conclusions:ERG+ tumors manifest clinically at lower PSA levels and their prevalence is age dependent. This suggests acceleration of tumor development by ERG overexpression that results in earlier tumor detection in young patients. Long-term results are warranted to determine the impact of ERG overexpression on disease outcome. [ABSTRACT FROM AUTHOR]

Purpose: Disorders of sex (DSD) development represent a serious condition. Most of the underlying mechanisms remain unclear. Disturbances within the androgen receptor (AR) pathway frequently account for 46 XY-DSDs. The individual gender-related outcome often is unsatisfactory. We present a long-term AR gene-mutation-associated follow-up in a group of 46 XY-DSD patients. Methods: Twenty patients (46 XY) who underwent genitoplasty in infancy or early childhood were retrospectively identified. Median follow-up after surgery was 16 years. All were undervirilized at initial presentation. Thirteen had female gender assignment, and 7 were raised as males. A genital skin biopsy and subsequent fibroblast cultures were done. The specific binding of dihydrotestosterone, the thermostability of the receptor hormone complex, and 5-α-reductase activity were measured. AR gene mutations were detected by direct sequencing. The individual outcome was correlated with specific AR mutations. Results: AR point mutations were detected in 12, 7 were previously unknown. There was no specific androgen binding in 3, reduced affinity in 9, and normal binding in 8 patients. 5-α-Reductase activity was normal in 15, reduced in 4 and completely absent in 1 patient. Conclusions: Retrospective evaluation revealed previously unknown and established AR gene mutations being associated with a distinct long-term outcome. Identification of the molecular mechanisms causing DSD will likely improve timely diagnosis and therapy. Exact characterization of AR activation and function may offer a treatment modality in affected patients. These data may allow us to give prognostic estimations on the individual outcome adding objective criteria for gender assignment in 46 XY-DSD patients. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor (IGF) and insulin (INS) proteins regulate key cellular functions through a complex interacting multi-component molecular network, known as the IGF/INS axis. We describe how dynamic and multilayer interactions give rise to the multifunctional role of the IGF/INS axis. Furthermore, we summarise the importance of the regulatory IGF/INS network in cancer, and discuss the possibilities and limitations of therapies targeting the IGF/INS axis with reference to ongoing clinical trials concerning the blockage of IGF1R in several types of cancer. [ABSTRACT FROM AUTHOR]

During the 10th week of gestation human prostate development is about to start. Androgens are the crucial factors to stimulate the initial interactions between the epithelium and mesenchyme. One of the key events in androgen metabolism is the transformation of circulating testosterone to 5α-dihydrotestosterone (DHT) by tissue-linked 5α-reductase. Both, the formation of a male phenotype and the androgen-mediated growth of the prostate are mediated by DHT. To date the function of 5α-reductase 1 (5αR1) still remains unclear whereas 5α-reductase 2 (5αR2) is supposed to be the predominant isoenzyme in human accessory sex tissue. Only little data are available on the detection, distribution, and effects of both isoenzymes during fetal life and infancy. Recently, immunohistochemical investigations of serial sections from fetuses and infants using specific antibodies directed against 5αR1 and 5αR2 seem to shed light on that issue. Moreover, the detection of downstream products of androgen synthesis using RT-PCR analyses for 17-β hydroxysteroid dehydrogenase Type 2 (17 βHSD 2), 17 βHSD Type 3 and 17 βHSD Type 7 adds to discovering the molecular biological background. New studies confirm that both isoenzymes are present throughout fetal development. On the transcriptional level RT-PCR for 5αR1 and 5αR2 certifies these findings. 17 βHSD 2, 3 and 7 representing the most relevant enzymatic downstream products of cellular androgen synthesis were revealed by RT-PCR as well. Current studies discovered the expression and distribution of both 5α-reductase isoenzymes as well as the potential contribution of 5αR1 during fetal human prostate development. [ABSTRACT FROM AUTHOR]

A thoroughly tested, high-temperature channel-die compression (CDC) rig is described for simulating hot plane strain compression of metallic alloys up to 500 °C. The equipment is currently used to characterize the flow stress and microstructure evolution in hot-rolled Al alloys. It has been validated by several tests involving (1) metallographic analysis of deformed samples; (2) flow stress comparisons with the same, or similar alloys deformed in conventional uniaxial or plane strain compression; and (3) microstructure and texture measurements. The use of modern lubricants enables one to obtain accurate flow stresses and true plane strain deformations that are homogeneous over 80 pct of the sample. The equipment also features rapid heating and cooling systems to minimize thermally-induced microstructure changes. Some results on high-temperature slip systems, hot deformation textures, and microstructures, and the behavior of constituent particles are outlined to illustrate the advantages of the technique. [ABSTRACT FROM AUTHOR]

Background: The type IV collagenases/gelatinases matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) play an important role in cancer invasion and metastasis. In the present study, we measured the expression of mRNAs and enzymatic activities of MMP-9 and -2 in prostate tissues and serum samples from men with or without prostate cancer.Methods: A total of 44 tissue samples (three from healthy volunteers, 21 from patients with benign prostate hyperplasia, 10 from patients with localized prostate cancer and 10 from patients with metastatic disease) and 71 serum samples were collected (20 from healthy volunteers, 26 from patients with benign prostatic hyperplasia, 10 from patients with localized cancer, 15 from patients with metastatic cancer). The level of mRNA for MMP-2 and -9 was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The enzymatic activity of MMPs was determined by zymography.Results: Expression of MMP-9 mRNA was significantly higher in malignant than in nonmalignant prostate tissues (P<0.001), while no significant difference of MMP-2 expression was detected in different prostate tissues. Results of zymography showed that there was significant difference in the enzymatic activity of MMP-9, but not MMP-2, among normal prostate, BPH, localized and metastatic prostate cancer tissues, serum samples (P<0.05). The active form of MMP-2, with a molecular mass of 62?kDa, was detected in normal prostate, BPH and prostate cancer tissues, but not in the serum samples. Moreover, there was a significant difference in the ratio of the active form (62?kDa) and proform (72?kDa) of MMP-2 among normal, BPH and prostate cancer tissues. This ratio was further increased in metastatic prostate cancer tissues.Conclusion: The activity of MMP-9 and the ratio of active form/proform of MMP-2 are associated with the progression and metastasis of prostate cancer.Prostate Cancer and Prostatic Diseases (2004) 7, 327-332. doi:10.1038/sj.pcan.4500750 Published online 7 September 2004 [ABSTRACT FROM AUTHOR]

Because of the heterogeneity of prostate cancer knowledge about the genes involved in prostate carcinogenesis is still very limited. Previously, the use of novel high-throughput technologies offered the possibility to investigate broad gene expression profiles and thus helped to improve understanding of the molecular basis of prostate disease. Many candidate genes have been identified so far which have a more or less strong effect on prostate cancer. This vast number of gene expression changes show that it is unlikely that only one gene promotes prostate cancer. Conversely, it seems more likely that a broad network of molecular changes is involved in the complex cascade of events which lead to tumour formation and progression, respectively. A few of these novel molecular targets are currently under clinical evaluation. This paper gives an overview of several interesting candidate genes which may be useful as improved biomarkers for diagnosis or as targets for developing novel treatment methods. [ABSTRACT FROM AUTHOR]

The genesis of benign prostate hyperplasia (BPH) depends on two factors: testicular androgen and the aging process. The most important androgen in the prostate is dihydrotestosterone (DHT). In the aging male the level of DHT in the prostate remains largely constant although the plasma level of testosterone decreases. DHT is formed by the reduction of testosterone by the enzyme 5-alpha-reductase, which has two isoenzymes. The 5-alpha-reductase type 2 is the predominant isoenzyme in genital tissue and thus also in the prostate. Finasteride is a 5-alpha-reductase inhibitor, which is applied in the treatment of BHP and male baldness. In the doses used finasteride acts mainly by inhibiting the 5-alpha-reductase type 2, thereby reducing the serum level of DHT by approximately 70% and by about 85-90% in the prostate. Indeed the effect of finasteride in BPH was proven in clinical studies. However, the circulating and intraprostatic DHT could be further reduced by a more effective dual 5-alpha-reductase inhibitor, which would be efficacious in the treatment of benign prostate hyperplasia and other DHT-related disorders. [ABSTRACT FROM AUTHOR]

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The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5α-reductase have been discovered. Type 1 is present in most tissues in the body where 5α-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5α-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5α-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5α-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%–90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5α-reductase. The suppression of both 5α-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5α-reductase. Physiological and clinical studies comparing dual 5α-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5α-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5α-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5α-reductase inhibitors may help to define the relative roles of human type 1 and 2 5α-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR), a key nuclear transcription factor in the prostate gland, is expressed in all histological types and stages of prostate cancer. The AR regulates proliferation of prostate cancer cells by stimulation of cyclin-dependent kinases. However, in some prostate tumors AR stimulates expression of cell cycle inhibitors, thus leading to down-regulation of cellular proliferation. Androgens, by activation of the AR, control differentiation of prostate cells and synthesis of neutral lipids. There are several mechanisms by which prostate cancer cells adapt to an environment with low androgen supply during endocrine therapy. The AR expression and activity increase in several cell lines that are used as an in vitro model for monitoring changes during long-term androgen ablation. Mutant ARs are of importance for monitoring the natural course of the disease and for determining the response to anti-androgens in metastatic lesions from prostatic carcinoma. In addition, AR activity is up-regulated by various stimulators of intracellular protein kinases. Current research efforts are focused on elucidation of function of AR coregulatory proteins, coactivators and corepressors. Their inappropriate expression and/or function might critically influence cellular events in advanced carcinoma of the prostate. It is hoped that information on these coregulatory proteins will serve as a basis for a more efficient pharmacological inhibition of the AR in advanced carcinoma of the prostate. [ABSTRACT FROM AUTHOR]

Interactions between polypeptide growth factors and the androgen receptor (AR) are important for regulation of cellular events in carcinoma of the prostate. Basic fibroblast growth factor (bFGF), the prototype of heparin-binding growth factors, and the AR are commonly expressed in prostate cancer. bFGF diminished prostate-specific antigen protein in the supernatants of androgen-stimulated human prostate cancer cells LNCaP by 80%. In the present study, we asked whether the bFGF effect on prostate-specific antigen is preceded by action on AR expression. LNCaP cells were treated with bFGF and AR protein expression was determined by immunoblotting and ligand binding assay. bFGF down-regulated AR protein in a dose-dependent manner showing a maximal effect at 50 ng ml[SUP-1] both in the presence or absence of dihydrotestosterone. Down-regulation of AR protein expression occurred already after 8 h of bFGF treatment and a maximal inhibition was observed 24 h after addition of bFGF to culture media. As AR expression can be reduced by an increase in intracellular calcium levels, we investigated whether the bFGF effect on AR protein is mediated by this mechanism. Calcium release from intracellular stores and store-operated calcium influx after treatment with either bFGF or calcium ionophore A 23187 were measured by single cell fluorescence technique. The ionophore A 23187 was able to induce calcium influx and an increase in cytoplasmic calcium concentration in LNCaP cells. In contrast, bFGF was incapable of eliciting a similar effect. In contrast to AR protein, AR mRNA levels were not affected by bFGF as shown by semiquantitative reverse transcription polymerase chain reaction. In summary, these studies show that bFGF is a potent negative regulator of AR protein expression in the human prostate cancer cell line LNCaP. [ABSTRACT FROM AUTHOR]

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In... [ABSTRACT FROM AUTHOR]

The effect and expression of amphiregulin, a growth factor of the EGF-system was investigated in prostate primary cell cultures and in human prostate tissue. Amphiregulin increases proliferation in primary cultures of prostate myofibroblasts grown in serum-free medium. Amphiregulin mRNA is expressed in high amounts in primary cell cultures of prostate myofibroblasts, fibroblasts, epithelial cells, and in samples of prostate tissue. The data are supported by Western-blotting of amphiregulin in prostate myofibroblasts. These data call for a refocus of the expression and effects of the EGF system in the prostate. [ABSTRACT FROM AUTHOR]

Adrenal androgens are discussed as a reason for tumor progression after androgen ablation therapy. Because of the difference in the secretion of androgens by the adrenals of humans and rats, there is no reliable tumor model to study the role of adrenal androgens in tumor progression. Therefore, the main adrenal androgens were administered to rats in order to mimic human endocrine conditions. Application of dehydroepiandrosteron-sulfate (DHEA-S) alone or a mixture of androstendione (A), 11β-hydroxyandrostendione (OHA), dehydroepiandrosterone (DHEA), and its sulfate (DHEA-S) to castrated rats caused only a slight increase of prostate and seminal vesicle weights. Contrary to these findings, growth of the R3327 prostatic carcinoma in castrated rats was greatly stimulated by these adrenal androgens up to the level of the intact control. Thus, in spite of androgen ablation, tumor progression could be induced by exogenous adrenal androgens. [ABSTRACT FROM AUTHOR]

The polypeptide growth factors insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor-α (TGF-α); second-messenger cyclic adenosine monophosphate (cAMP); protein kinase activators; and neurotransmitters were found to activate the estrogen (ER), progesterone (PR), and glucocorticoid receptor (GR) either in the absence of their natural ligands or synergistically with the respective hormone. There is now evidence of coupling of signaling pathways involving the androgen receptor (AR). Three polypeptide growth factors, IGF-I, keratinocyte growth factor (KGF), and EGF, stimulated AR-mediated reporter-gene transcription in the absence of androgen in DU-145 cells, which were cotransfected with the reporter gene and an AR expression vector. IGF-I effects were observed irrespective of the promoter driving the reporter gene. This growth factor increased the prostate-specific antigen (PSA) level in LNCaP cells, which contain endogenous AR. In CV-1 cells, which transiently express the AR, second-messenger cAMP potentiated effects of testosterone in stimulation of AR-mediated reporter-gene activity. Inhibition of androgen-stimulated chloramphenicol acetyltransferase (CAT) activity in the LNCaP cell line was achieved with retinoic acid. Stimulation and inhibition of prostatic carcinoma cell growth by polypeptide growth factors and cellular regulators may depend on the presence of the AR in an androgen-depleted environment. [ABSTRACT FROM AUTHOR]

In the prostate, androgen action affects the growth of the gland, its morphology, and regulation of protein expression. Endocrine therapy of non-organ-confined tumors is based on the androgen dependence of the vast majority of prostatic carcinomas. Although initial response rates are high, this therapy is only temporarily effective. Critical molecular changes ultimately resulting in androgen independence of tumor cells are unknown at this time. The androgen signal-transduction cascade and its central element, the androgen receptor (AR), are possible targets for such changes. Immunohistological analysis using anti-AR antibodies has revealed the presence of AR in a vast majority of therapy-responsive as well as therapy-unresponsive prostatic carcinomas, indicating that loss of AR expression is not the reason for androgen independence. On the other hand, molecular-biology studies have revealed qualitative and quantitative impairment of AR expression in prostatic tumor cell lines that represent very late stages of prostatic carcinoma development. Mutant ARs were detected in the prostatic tumor cell line LNCaP and in two specimens from primary prostatic tumors. The LNCaP mutant AR as well as mutant AR715met, one of the mutant receptors detected in tumor tissue, show a gain of function as compared with the wild-type receptor. In addition to androgens, the natural activators of the AR, the LNCaP receptor is activated also by progestagenic and estrogenic steroids and by the nonsteroidal antiandrogen flutamide. AR715met is activated by adrenal androgens and progesterone in addition to androgens. Although determination of the frequency of point mutations in late prostatic carcinoma requires further investigation, these data imply that tumor progression in an androgen-ablated environment may be accompanied by aberrant AR activation. [ABSTRACT FROM AUTHOR]

A correction to the article "Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor," by I. E. Eder and colleagues that was published in the previous issue is presented.