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Androgen Withdrawal (androgen + withdrawal)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Protein tyrosine phosphatase PTP1B is involved in neuroendocrine differentiation of prostate cancer

THE PROSTATE, Issue 11 2006
Chengyu Wu
Abstract BACKGROUND Prostate cancer (PC) contains a minor component of neuroendocrine (NE) cells that may stimulate androgen-independent growth of the tumor. The mechanism of neuroendocrine differentiation remains unknown. METHODS The expression of PTP1B, a protein tyrosine phosphatase, was studied in LNCaP cells induced to show neuroendocrine phenotype by androgen withdrawal. Wild-type PTP1B and its dominant-negative mutant were transfected into LNCaP cells to study their effects on neuroendocrine differentiation. In vivo expression of PTP1B in human prostate cancer was studied by immunohistochemistry. RESULTS Androgen withdrawal of LNCaP cells led to increased expression of PTP1B with a corresponding increase in its tyrosine phosphatase activity. Overexpression of PTP1B in LNCaP cells led to neuroendocrine differentiation while expression of its dominant-negative mutant inhibited neuroendocrine differentiation. Immunohistochemical study showed that PTP1B was exclusively expressed in neuroendocrine cells of human prostate cancer tissue. Conclusion Our findings suggest that PTP1B plays an important role in neuroendocrine differentiation, and therefore, may possibly be involved in the progression of prostate cancer. Prostate © 2006 Wiley-Liss, Inc. [source]

Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic

INTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2005
HIDEAKI MIYAKE
Abstract Background The objective of this study was to review our experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy for prostate cancer targeting antiapoptotic gene, clusterin. Methods We initially summarized our data demonstrating that clusterin could be an optimal therapeutic target for prostate cancer, then presented the process of developing AS ODN therapy using several preclinical animal models. Finally, the preliminary data of the recently completed phase I clinical trial using AS clusterin ODN as well as the future prospects of this therapy are discussed. Results Expression of clusterin was highly up-regulated after androgen withdrawal and during progression to androgen-independence, but low or absent in untreated tissues in both prostate cancer animal model systems and human clinical specimens. Introduction of the clusterin gene into human prostate cancer cells confers resistance to several therapeutic stimuli, including androgen ablation, chemotherapy and radiation. AS ODN targeting the translation initiation site of the clusterin gene markedly inhibited clusterin expression in prostate cancer cells in a dose-dependent and sequence-specific manner. Systemic treatment with AS clusterin ODN enhanced the effects of several conventional therapies through the effective induction of apoptosis in prostate cancer xenograft models. Based on these findings, a phase I clinical trial was completed using AS clusterin ODN incorporating 2,-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), showing up to 90% suppression of clusterin in prostate cancer. Conclusions The data described above identified clusterin as an antiapoptotic gene up-regulated in an adaptive cell survival manner following various cell death triggers that helps confer a phenotype resistant to therapeutic stimuli. Inhibition of clusterin expression using AS ODN technology enhances apoptosis induced by several conventional treatments, resulting in the delay of AI progression and improved survival. Clinical trials using AS ODN confirm potent suppression of clusterin expression and phase II studies will begin in early 2005. [source]

Androgen-independent expression of adrenomedullin and peptidylglycine ,-amidating monooxygenase in human prostatic carcinoma

MOLECULAR CARCINOGENESIS, Issue 1 2003
Nuria Jiménez
Abstract Most of the locally advanced and metastatic prostate carcinomas (PCs) treated with antiandrogenic therapy eventually become refractory to this treatment. Locally produced factors may control prostate tumor biology after androgen withdrawal. Adrenomedullin (AM) is expressed in the prostate and could control cell growth in androgen-independent conditions. AM needs to be amidated by the enzyme peptidylglycine ,-amidating monooxygenase (PAM) to become fully active. The objective of the present study was to analyze whether the expression of preproadrenomedullin (preproAM) and PAM in PC is regulated by androgens. For this purpose, human in vitro and in vivo PC models were grown in the presence or absence of androgens, and the expression of AM and PAM was examined by immunohistochemistry, Western blotting, RT-PCR, and Northern blotting. Furthermore, immunohistochemical analysis of AM in clinical specimens was performed to test if its expression is related to Gleason score and antiandrogenic therapy. In PC cell lines and xenografts, mRNA and protein AM levels were similar in the presence or absence of androgens. PAM expression seemed to be induced by androgen-withdrawal. Our results in clinical samples showed no relationship between AM expression and Gleason score or antiandrogenic treatment. In conclusion, our results demonstrate that preproAM and PAM expression in the human prostate is androgen-independent. In addition, we also report for the first time the expression of a novel PAM transcript in PC, which has not been previously described in other tissues. © 2003 Wiley-Liss, Inc. [source]

Protein tyrosine phosphatase PTP1B is involved in neuroendocrine differentiation of prostate cancer

Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: Association with tumor cell proliferation prior to recurrence

THE PROSTATE, Issue 2 2004
Wendy J. Huss
Abstract BACKGROUND Neuroendocrine (NE) cell differentiation is proposed to facilitate prostate cancer (CaP) recurrence following androgen deprivation through secretion by NE cells of growth factors and neuropeptides that support survival and proliferation of CaP cells and vasculature. METHODS The effect of androgen deprivation on NE differentiation and tumor cell proliferation in the CWR22 model of human CaP was determined by immunohistochemical analysis of the NE cell marker synaptophysin and the cell proliferation marker Ki67. RESULTS A significant increase in the number of NE cells was observed in CWR22 tumors between 28 and 66 days after castration compared to intact mice, that preceded the increase in tumor cell proliferation that began 70 days after androgen deprivation heralding recurrence. There was a significant positive correlation between the number of tumor-associated NE cells and proliferating CaP cells in tumors from mice after 28,34 days of androgen withdrawal. CONCLUSION In the CWR22 model, androgen deprivation induces an increase in tumor-associated NE cells prior to increased tumor cell proliferation, with NE cells possibly promoting tumor survival and recurrent disease. © 2004 Wiley-Liss, Inc. [source]

The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer

BJU INTERNATIONAL, Issue 1 2000
R. Kurek
Objectives,To compare the serum levels of insulin-like growth factor-1 (IGF-1) in patients with prostate cancer and in control patients with no malignancy, and to evaluate any possible influence of testicular androgen withdrawal on the level of IGF-1 in patients with prostate cancer. Patients and methods,IGF-1 was measured in serum samples from 238 patients using both a chemiluminescence method and a radio-immunoassay. From a subgroup of 19 patients presenting with newly diagnosed carcinoma of the prostate, IGF-1 and testosterone values were measured before and during the course of testicular androgen with-drawal, achieved by the administration of luteinizing hormone-releasing hormone (LHRH) analogues combined with anti-androgens. Results,There were no significant differences in the mean serum levels of IGF-1 patients with and without prostate cancer (158.6 and 159.1 ng/mL, respect-ively). There were no significant differences in mean IGF-1 levels before and after antiandrogen therapy; the mean (median, sd, range) levels of testosterone (µg/L) and IGF-1 (ng/mL) before androgen withdrawal were 4.81 (4.84, 1.26, 3.11,6.93) and 157.1 (152.5, 26.7, 122.8,195.1). After androgen withdrawal the corresponding values were 0.303 (0.218, 0.24, 0.13,0.81) and 169.7 (31.7, 168.6, 124.9,227.6). A linear regression analysis (P = 0.76) and Spearman rank order correlation test (correlation coefficient ,0.0613, P = 0.64) showed no association between levels of testosterone and IGF-1. Freeze and thaw cycles applied to the samples had no effect on the IGF-1 values measured. Conclusions,There was no significant association between IGF-1 serum levels and prostate cancer. Short-term androgen withdrawal using LHRH anal-ogues combined with anti-androgens had no effect on the levels of IGF-1. [source]