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Clinical Genitourinary Cancer 11/2011; 10(1):47-9. · 2.61 Impact Factor
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ABSTRACT: The role of neuroendocrine (NE) cells in prostate cancer biology remains unclear. We previously reported a large difference in NE expression in benign prostate tissue among men of different ethnicities; African-American men had significantly fewer NE cells compared to all other groups. This report describes NE expression in malignant prostate tissue.
Paraffin-embedded tissue from 180 men who underwent radical prostatectomy at the University of Southern California between 1983 and 2003 was stained using standard immunohistochemistry technique for chromogranin A (ChrA), serotonin (Ser) and synaptophysin (Syn). There were 39 specimens from African-American patients, 39 Asian, 57 Hispanic and 45 non-Hispanic White. Staining intensity and the percentage of cells positive were determined by the automated cellular imaging system. Results were analyzed by univariate and multivariate general linear regression models.
There were significant differences in staining intensity for all markers between ethnic groups in univariate analysis. NE expression, judged by ChrA intensity, was highest in Hispanic patients, compared to non-Hispanic Whites and African-Americans. A similar pattern was observed for Syn and Ser. In multivariate analysis, controlling for age, Gleason score, PSA and stage, the differences in ChrA, Syn and Ser remained highly significant. Hispanic men had higher ChrA expression levels than African-Americans and non-Hispanic Whites (p=0.0077 and 0.0038, respectively); the p-values for the comparison were both <0.0001 for Ser. Both Hispanic and Asian patients had higher intensity Ser expression than African-American and Non-Hispanic Whites patients, with all p-values <0.018.
As already shown in benign prostate tissue, we identified significant differences in NE expression among prostate cancer tissues from men of different ethnic backgrounds. The clinical impact of these differences in NE expression warrants exploration.
Anticancer research 11/2011; 31(11):3897-901. · 1.73 Impact Factor
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Acta Haematologica 09/2011; 126(4):240. · 1.35 Impact Factor
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ABSTRACT: Recent data has shown that prostate cancer (PCA) cells are capable of producing testosterone directly from cholesterol, which may contribute to the development of castration resistance. While up-regulation of steroidogenic enzymes has been previously described during castration-resistant prostate cancer (CRPC) progression, regulation of this process is poorly defined. These data examine the role of luteinizing hormone (LH) in the regulation of steroidogenic machinery in PCA cells.
PCA cell lines LNCaP, C4-2B, and 22RV1 were exposed to LH. Gene expression was quantified using real-time PCR and protein expression was characterized with standard Western blot analysis. Steroid analysis was performed using radioimmunoassay (RIA). Cell viability was measured using an MTS viability assay.
Androgen-sensitive (LNCaP) and -independent PCA cells (C4-2B and 22RV1) express both mRNA and protein for LH and LH receptor (LHR). Exposure of these cells to LH for 4 hr increased the expression of several steroidogenic genes. Exposure for 10 days resulted in the increase of additional genes. At both time points, the upregulation of these genes was dose-dependent. This was mirrored by an increase in the expression of several key steroidogenic enzymes, including StAR, CYB5B, CYP11A, and 3βHSD. LH stimulated the production of progesterone and testosterone in LNCaP cells as measured by RIA. We have also demonstrated that treatment of LNCaP cells with LH enhanced their viability.
Our data show that LH-mediated activation of LHR significantly up-regulates the expression of genes and enzymes required for steroidogenesis and increases steroid production in PCA cells.
The Prostate 06/2011; 71(8):892-8. · 3.48 Impact Factor
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Acta Haematologica 04/2011; 126(2):76-8. · 1.35 Impact Factor
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ABSTRACT: INTRODUCTION: Receptors for luteinizing hormone-releasing hormone (LHRH) are expressed on a variety of human cancer cells with relatively limited expression in normal tissues. The selective and persistent expression of these receptors in prostate cancer cells is the rationale for LHRH receptor targeted agents. With many agents in development and one entering early clinical study, it is important to be familiar with the concept of LHRH receptor targeting and the evidence supporting its use. AREAS COVERED: This manuscript reviews the expression of LHRH receptors and the rationale for LHRH receptor targeted therapy in prostate cancer. Several different classes of agents targeting the LHRH receptor are discussed. The preclinical evidence supporting these agents is also reviewed and the clinical trial testing one of these agents is detailed. EXPERT OPINION: LHRH receptor expression on prostate cancer cells has led to the rational design of many new compounds. The preclinical evidence is encouraging for these agents, which are in varying phases of development. AN-152 combines a modified LHRH agonist carrier with doxorubicin and is entering a Phase I-II clinical study.
Expert Opinion on Investigational Drugs 03/2011; 20(6):769-78. · 5.27 Impact Factor
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Stephen V Liu,
Andrew V Schally,
Debra Hawes,
Shigang Xiong,
Laden Fazli,
Martin Gleave,
Jie Cai,
Susan Groshen,
Frank Brands,
Juergen Engel,
Jacek Pinski
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ABSTRACT: In addition to their expression on pituitary cells, receptors for luteinizing hormone-releasing hormone (LH-RH) are found on most prostate cancer cells. These tumoral LH-RH receptors mediate the direct cytotoxic effects of LH-RH analogs and are potential therapeutic targets. Although pituitary LH-RH receptors are downregulated following prolonged exposure to LH-RH agonists, there is no evidence that tumoral receptors behave in a similar manner. To better characterize expression of tumoral LH-RH receptors, specimens of prostate cancer from various cohorts of patients were analyzed.
Surgical specimens were obtained from untreated patients with prostate cancer and from patients with metastatic castration-resistant prostate cancer previously treated with bilateral orchiectomy. To address the possibility of receptor downregulation, two additional cohorts of patients who had been previously treated with LH-RH agonists were included. One group received neoadjuvant therapy prior to prostatectomy, and the other group was treated for metastatic disease with LH-RH agonists and, at progression, required palliative resection of the prostate. Lymph node metastases from previously untreated patients were subjected to similar analysis.
Expression of LH-RH receptors was found in most specimens. The relative expression of LH-RH receptor mRNA in untreated patients was greater in patients whose tumor had received a Gleason score <8.
LH-RH receptor expression persisted despite prolonged exposure to LH-RH agonists. These findings support the concept of targeting cytotoxic LH-RH analogs to prostatic LH-RH receptors, using these receptors to gain entry into cancer cells to deliver a hybridized cytotoxic moiety for the treatment of prostate cancer.
Clinical Cancer Research 09/2010; 16(18):4675-80. · 7.74 Impact Factor
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ABSTRACT: The past few decades have seen an increase in both the role and the complexity of neoadjuvant therapy for breast cancer. Neoadjuvant therapy was initially described as systemic chemotherapy for inflammatory or locally advanced breast cancer but now entails a combination of chemotherapy, endocrine therapy, and targeted therapy. Neoadjuvant systemic therapy is employed for inoperable inflammatory and locally advanced breast cancer, and also for patients with operable breast cancers who desire breast-conserving therapy (BCT) but are not candidates based on the initial size of the tumor in relation to the size of the breast. Neoadjuvant therapy in this subset of patients may impact the surgical options. This review will summarize the benefits of neoadjuvant systemic therapy and implications for BCT, the timing of sentinel node biopsy, and the utility of magnetic resonance imaging (MRI) to predict response to therapy.
Journal of Surgical Oncology 02/2010; 101(4):283-91. · 2.10 Impact Factor
