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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28

Perineal needle tract seeding of prostate cancer is an unusual complication of perineal prostate biopsy. We report a case with the longest known interval from biopsy to perineal recurrence--14 years. The prostate-specific antigen did not become detectable until 12 years after biopsy and no other metastases were apparent, suggesting that the patient's perineal disease was an isolated recurrence. Immunohistochemical staining of the perineal recurrence and the original biopsy and prostate for the p53 tumor suppressor gene and bcl-2 oncogene proteins revealed rare/absent p53 expression but marked increased bcl-2 expression. This unusual molecular pedigree may help to explain this rare clinical scenario.
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PMID:Perineal seeding of prostate cancer as the only evidence of clinical recurrence 14 years after needle biopsy and radical prostatectomy: molecular correlation. 945 12

Prostate-specific antigen (PSA) is expressed in normal, hyperplastic and cancerous female breast tissue. Expression is regulated by steroid hormones. Some breast tumours produce very high levels of PSA, while other do not express any PSA. In this study, we selected three primary breast tumours which overexpressed PSA (PSA protein concentration in tumour cytosols > 4300 ng/l) and three tumours which were negative for PSA (< 1 ng/l). We extracted DNA and sequenced all five exons of the PSA gene. No mutations were found in the PSA coding sequence in any of the tumours. We identified only two polymorphic sites in exon 2. We also sequenced parts of the 5' flanking region of the PSA gene in five tumours. All tumour DNAs contained abnormalities which consisted of point mutations and deletions of 1-7 base pairs. Except for one tumour which had only a 3 base pair deletion, all other tumours had multiple abnormalities (up to seven in one tumour). The deletions occurred adjacent to direct repeats similarly to deletions seen in the p53 gene. Our data suggest that the coding sequence of PSA is not mutated in breast cancer. However, the 1.4 kb 5'-flanking region was mutated in all five tumours tested. The importance of this observation in relation to PSA gene regulation and breast cancer pathobiology remain to be determined.
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PMID:Frequent detection of mutations in the 5' flanking region of the prostate-specific antigen gene in female breast cancer. 947 Aug 45

Current dilemmas for physicians managing patients with localized prostate cancer include deciding: (1) which patients need aggressive treatment; (2) what treatment options are best for a given patient; and (3) what treatment outcomes can be expected. This article reviews our ability to prognosticate outcome (including pathological stage and disease-free survival rate) in patients with clinically localized adenocarcinoma of the prostate (AJCC, stage T1-T2. N0, M0) subsequent to analysis of several contemporary series involving patients treated with radical prostatectomy and external-beam radiation therapy. Pretherapy prostate-specific antigen (PSA) level (< or =4 ng/mL or >20 ng/mL) and Gleason score (< or =4 or > or =8) as individual variables provide independent prognostic information for only a subset of patients undergoing radical prostatectomy and external-beam radiation therapy. Pathological stage is the most powerful predictor of outcome following radical prostatectomy, and its prediction (organ-confined vs. seminal vesicle or lymph node involvement) is aided by knowledge of clinical stage, Gleason score, and PSA level. Planned systematic biopsies also provide useful prognostic information for the prediction of pathological stage and tumor volume, as well as providing additional tissue for pathological assessment of tumor heterogeneity. Several novel markers of biological aggressiveness are associated with critical steps of the metastatic cascade (growth, invasion, angiogenesis, and resistance to apoptosis) and include the p53 tumor suppressor gene, the bcl-2 proto-oncogene, markers of increased proliferation (Ki-67), apoptosis, and angiogenesis (microvessel density). Their evaluation in clinical specimens is currently being used to prognosticate outcome. Current clinical and pathological parameters provide a "ballpark" estimate of outcome for patients with clinically localized prostate cancer. Further elucidation of the critical molecular events associated with prostate cancer progression and metastasis should help in identifying molecular markers that more accurately predict the prognosis for an individual patient with clinically localized prostate cancer.
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PMID:Prognostic markers in clinically localized prostate cancer. 956 75

Tumor biomarkers (p53, bcl-2, Ki-67, and RT-PCR) were reviewed in the literature for their ability to predict prostate-specific antigen (PSA) biological recurrence after radical prostatectomy. All of them are strongly associated with PSA recurrence on univariate analysis. p53 seems to be better than current predictors, such as stage, grade, and positive surgical margins on multivariable analysis; further studies need to confirm bcl-2 and Ki-67 as better predictors of PSA recurrence. However, most of these studies were performed on radical prostatectomy specimens and will need to be confirmed on the preoperative prostate biopsy. The RT-PCR assay was strongly correlated with PSA recurrence and was one of the two best preoperative PSA recurrence predictors with serum PSA.
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PMID:The role of tumor biomarkers as predictors of serum PSA recurrence after radical prostatectomy. 974 18

Immunohistochemical (IHC) staining for p53 protein nuclear expression was evaluated in archival paraffin-embedded radical prostatectomy specimens from 139 patients with clinically localized prostate cancer followed up from 1 to 8 (mean, 4) years. Elevated nuclear p53 protein expression was detected in 85 (61%) of 139 patients, being heterogeneous and focal in the majority of specimens. Only four specimens displayed homogeneous nuclear accumulation of p53 protein. Disease progression, most commonly prostate-specific antigen elevation, was noted in 46 (33%) patients, with 39 (85%) having positive p53 protein IHC stains. Conversely, 93 (67%) of 139 have not recurred, with 46 (49%) having positive p53. Of all 54 p53-negative patients, 47 (87%) have had no disease recurrence. An increased p53 protein IHC stain was associated with a higher pathological stage (T1 and T2, 51% versus >/=T3, 69%) and Gleason score 2-4, 17%; 5-7, 72%; and 8-10, 87.5%). Despite these associations, p53 IHC staining was an independent predictor of disease-free survival in a multivariate analysis of p53, age, race, stage, and grade. This study revealed that a majority of clinically localized prostate cancers heterogeneously express elevated nuclear levels of p53 protein in at least a subset of malignant cells, and that this expression is an independent predictor of disease progression in prostate cancer patients after radical prostatectomy.
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PMID:p53 nuclear protein expression is an independent prognostic marker in clinically localized prostate cancer patients undergoing radical prostatectomy. 981 24

Because of histological similarities between nephrogenic adenomas and clear cell adenocarcinomas of the urinary tract, there is the potential for diagnostic confusion between these two entities. The histopathologic features of 13 nephrogenic adenomas and five clear cell adenocarcinomas of the urethra and urinary bladder are compared in this report, and detailed immunohistochemical staining profiles are provided for these tumors. Only 2 of the 13 nephrogenic adenomas contained clear cells, and these constituted less than 10% of the lesions. In contrast, four of the five clear cell adenocarcinomas contained prominent areas with clear cells. Nephrogenic adenomas generally showed only mild cytologic atypia, whereas four of the five clear cell adenocarcinomas showed severe atypia. A single mitotic figure was identified in only two of the nephrogenic adenomas, whereas the mitotic rate in the clear cell adenocarcinomas ranged from 2 to 14 per 10 high-power fields. None of the nephrogenic adenomas showed evidence of necrosis, but focal necrosis was noted in four of the five clear cell adenocarcinomas. In general, the nephrogenic adenomas and clear cell adenocarcinomas showed negative to weak staining with CK903 but strong staining with AE1, AE3, and Cam 5.2. Variable staining was observed with Brst-3 and antibodies to S-100, CEA (monoclonal and polyclonal), LeuM-1, and CA19.9. Nephrogenic adenomas and clear cell adenocarcinomas were all negative for prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and estrogen and progesterone receptors (except for two nephrogenic adenomas, which showed only focal weak staining for estrogen receptor). Neither bcl-2 nor c-erbB-2 staining was able to discriminate between the tumors. However, strong staining for p53 was noted in each clear cell adenocarcinoma and in none of the nephrogenic adenomas. MIB-1 positivity in nephrogenic adenomas ranged from 0 to 13 (average of 5.5) per 200 cells, whereas the positive range for clear cell adenocarcinomas was 33 to 70 (average of 47) per 200 cells. In summary, histopathologic features that favor clear cell adenocarcinoma over nephrogenic adenoma include a predominance of clear cells, severe cytological atypia, high mitotic rate, necrosis, high MIB-1 positivity, and strong staining for p53.
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PMID:Clear cell adenocarcinoma and nephrogenic adenoma of the urethra and urinary bladder: a histopathologic and immunohistochemical comparison. 986 32

Streptavidin and antibodies were labeled with phosphorescent platinum and palladium coproporphyrin. The optimal conjugates were selected on the basis of spectroscopic analysis (molar extinction coefficient, quantum yield, lifetime) and using ELISA assays to determine the retention of biological activity and immunospecificity. They were subsequently tested for the detection of prostate-specific antigen, glucagon, human androgen receptor, p53, and glutathione transferase in strongly autofluorescent tissues. Furthermore, platinum and palladium coproporphyrin-labeled dUTPs were synthesized for the enzymatic labeling of DNA probes. Porphyrin-labeled DNA probes and porphyrin-labeled streptavidin conjugates were evaluated for DNA in situ hybridization on metaphase spreads, using direct and indirect methods, respectively. The developed in situ detection technology is shown to be applicable not only in mammals but also in plants. A modular- based time-resolved microscope was constructed and used for the evaluation of porphyrin-stained samples. The time-resolved module was found suitable for detection of antigens and DNA targets in an autofluorescent environment. Higher image contrasts were generally obtained in comparison with conventional detection systems (e.g., fourfold improvement in detection of glutathione transferase).
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PMID:Phosphorescent platinum/palladium coproporphyrins for time-resolved luminescence microscopy. 988 54

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
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PMID:Overcoming bcl-2- and p53-mediated resistance in prostate cancer. 1019 Jul 92

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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PMID:Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. 1037 42


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