David T Price

Duke University Medical Center, Durham, North Carolina, United States

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Publications (10)28.08 Total impact

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    ABSTRACT: Development of new therapeutic modalities for human prostate carcinoma has been impeded by a lack of adequate in vitro and in vivo models. Most in vitro studies have been carried out using a limited number of human prostate cancer cell lines that are mostly derived from metastatic tumors sites or are immortalized. Characterization of the prostate cancer cell line, HH870, included description of morphology, determination of doubling time, response to androgens, immunocytochemistry, and immunoblotting of proteins known to be associated with prostate carcinoma, karyotyping, fluorescence in situ hybridization (FISH), DNA profiling, and growth as xenograft in athymic rodents. HH870 expresses various epithelial marker antigens that correlate with known basic immunostaining profiles of prostate adenocarcinoma, although the cell line does not express PSA, PSMA, or PAP. HH870 exhibits complex chromosomal abnormalities and harbors no immortalizing HPV, BKV, JCV, and SV40 DNA. We report the successful establishment and characterization of a new long-term primary human prostate tumor cell line HH870.
    The Prostate 05/2005; 63(1):91-103. · 3.84 Impact Factor
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    ABSTRACT: Benign prostatic hyperplasia is a common cause of urinary flow obstruction in aging men and may lead to lower urinary tract symptoms (LUTS). Benign prostatic hyperplasia has 2 physiological components: a static component related to increased prostate size and a dynamic component related to increased prostate smooth muscle tone. alpha1-Adrenoceptors (alpha1ARs) maintain prostate smooth muscle tone; hence, alpha1-antagonists (blockers) relax prostate smooth muscle and decrease urethral resistance, ultimately leading to relief of LUTS. This review focuses on alpha1AR subtypes and their location in lower urinary tract tissues involved in LUTS (prostate, bladder, spinal cord); it also summarizes major clinical trials published to date on the efficacy of alpha1AR blockers for LUTS. Benefits and adverse effects of clinically available alpha1AR antagonists are reviewed, followed by recent information on interactions between alpha1AR subtype antagonists and type 5 phosphodiesterase inhibitors used for impotence. alpha1-Adrenoceptor antagonists have become the mainstay of therapy for LUTS; knowledge about specific alpha1AR subtypes should facilitate rational choice of alpha1AR blocker therapy by clinicians.
    Mayo Clinic Proceedings 12/2004; 79(11):1423-34. · 5.79 Impact Factor
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    ABSTRACT: The most effective therapy for metastatic prostate cancer is androgen deprivation. Genes activated directly or possibly even indirectly by this steroid hormone represent potential targets for anticancer therapy. One such gene may be hTERT, which encodes the catalytic subunit of telomerase. In prostate cancer cells telomerase is activated, permitting sustained proliferation. Therefore, we tested whether hTERT gene expression is modulated in prostate cancer cells in vitro and in vivo by androgens. Transcriptional activation of hTERT during androgen stimulation was assayed by luciferase assays using the hTERT promoter fused to the luciferase gene and by reverse transcriptase-polymerase chain reaction to detect endogenous hTERT mRNA in LNCaP cells. hTERT mRNA levels and telomerase activity were also measured in CWR22 prostate cancer cells implanted in mice that were subsequently castrated and left untreated or administered androgen. We report that the endogenous hTERT promoter is activated during the administration of androgen to androgen sensitive LNCaP prostate cancer cells. However, this effect was indirect since an hTERT promoter construct was not activated by androgens and transcription of the endogenous gene was not stimulated early enough in cultured cells to be considered a direct target of this steroid hormone. Importantly in an in vivo model of human prostate cancer androgen deprivation led to a decrease in hTERT expression, followed by a decrease in telomerase activity, which was reversed by a single administration of androgen. The hTERT gene is regulated in human prostate cancer cells in vivo by androgens.
    The Journal of Urology 09/2003; 170(2 Pt 1):615-8. · 3.75 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) imaging is used for the metabolic evaluation of cancer. [18F]fluorodeoxyglucose (FDG) is commonly used as a radiotracer but its low cellular uptake rate in prostate cancer limits its usefulness. We evaluated the novel choline analog [18F]fluorocholine (FCH) for detecting androgen dependent and androgen independent prostate cancer, and its metastases. The cellular uptake of FCH and FDG was compared in cultured prostate cancer cells (LNCaP and PC-3). FCH and FDG were injected into nude mice xenografts (CWR-22 and PC-3) and radiotracer uptake in various organs were evaluated. Patients with androgen dependent (9) and independent (9) prostate cancer were studied by FCH and FDG PET. FCH uptake was 849% and 60% greater than FDG uptake in androgen dependent (LNCaP) and independent (PC-3) cells, respectively. The addition of hemicholinium-3 (5 mM.) 30 minutes before radiotracer administration inhibited FCH uptake by 79% and 70% in LNCaP and PC-3 cells, respectively, whereas FDG uptake was not significantly affected. Although nude mice xenografts showed that FDG uptake was equal to or greater than FCH uptake, clinical imaging in patients demonstrated 2 to 4-fold higher uptake of FCH in those with androgen and androgen independent prostate carcinoma (p <0.001). More lesions were detected by FCH than by FDG in primary tumors, osseous metastases and soft tissue metastases. In vitro data demonstrated greater FCH than FDG uptake in androgen dependent (LNCaP) and androgen independent (PC-3) prostate cancer cells. Although the murine xenograft data showed greater accumulation of FDG than FCH in PC-3 tumors, PET in humans showed that FCH was better than FDG for detecting primary and metastatic prostate cancer. Overall the data from this study suggest that FCH is preferable to FDG for PET of prostate carcinoma and support the need for future validation studies in a larger number of subjects.
    The Journal of Urology 07/2002; 168(1):273-80. · 3.75 Impact Factor
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    ABSTRACT: 18F-Fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) has been developed as an oncologic probe for PET. This study evaluates the kinetics and radiation dosimetry of 18F-FCH using murine and human biodistribution data. The biodistribution of 18F-FCH was obtained at time points up to 10 h after administration in control and tumor-bearing anesthetized nude mice. Human biodistribution data within the first hour after injection were obtained from attenuation-corrected whole-body PET scans of male (n = 7) and female (n = 5) cancer patients. Radiation dosimetry estimates were calculated using the murine and human biodistribution data assuming no redistribution of tracer after 1 h. Rapid pharmacokinetics were observed for 18F-FCH in mice and humans. The biodistribution is nearly static after 10 min. The dose-critical organ is the kidney, which receives 0.17 +/- 0.05 and 0.16 +/- 0.07 mSv/MBq (0.64 +/- 0.18 and 0.55 +/- 0.32 rad/mCi) for females and males, respectively. The effective dose equivalent (whole body) from administration of 4.07 MBq/kg (0.110 mCi/kg) is approximately 0.01 Sv for females and males. 18F-FCH is rapidly cleared from the circulation and its biodistribution changes very slowly at >10 min after administration. The kidney is the dose-critical organ and limits administration levels of 18F-FCH to 4.07 MBq/kg (0.110 mCi/kg) in human research studies.
    Journal of Nuclear Medicine 01/2002; 43(1):92-6. · 5.77 Impact Factor
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    ABSTRACT: Adrenergic receptors (ARs) are members of the G-protein-coupled receptor family, which includes α1ARs, α2ARs, β1ARs, β2ARs, β3ARs, adenosine, muscarinic, angiotensin, endothelin receptors, and many others that are responsible for a large variety of physiologic effects through G-protein coupling. This review focuses on α1ARs and their regulation at both the mRNA and protein levels. Currently, three α1AR subtypes have been characterized both pharmacologically and at the gene level: α1aAR, α1bAR, and α1dAR. These are expressed in a species- and tissue-dependent manner. Mutagenesis approaches have been extremely valuable in the identification of key residues that govern α1AR ligand binding and signaling. These studies reveal that α1ARs have evolved an exquisitely sensitive regulation of their activity in which any disruption of the native structure has profound effects on subsequent function and effector coupling. Significant advances have also been made in the elucidation of signaling pathway components, resulting in the identification of novel pathways that can lead to pathologic conditions. Specific topics include mitogen-activated protein kinase , phosphatidylinositol 3-kinase , and G-protein-coupled receptor cross-talk pathways. Within this context, recent studies identifying underlying transcriptional mechanisms involved in the regulation of the α1AR subtypes is also discussed. Finally, given the potentially important role of α1ARs in the vasculature, as well as in the pathology of many diseases, such as myocardial hypertrophy and benign prostatic hyperplasia, the clinical relevance of α1AR distribution, pharmacology, and therapeutic intervention is reviewed.
    Pharmacology & Therapeutics. 12/2000;
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    ABSTRACT: Adrenergic receptors (ARs) are members of the G-protein-coupled receptor family, which includes α1ARs, α2ARs, β1ARs, β2ARs, β3ARs, adenosine, muscarinic, angiotensin, endothelin receptors, and many others that are responsible for a large variety of physiologic effects through G-protein coupling. This review focuses on α1ARs and their regulation at both the mRNA and protein levels. Currently, three α1AR subtypes have been characterized both pharmacologically and at the gene level: α1aAR, α1bAR, and α1dAR. These are expressed in a species- and tissue-dependent manner. Mutagenesis approaches have been extremely valuable in the identification of key residues that govern α1AR ligand binding and signaling. These studies reveal that α1ARs have evolved an exquisitely sensitive regulation of their activity in which any disruption of the native structure has profound effects on subsequent function and effector coupling. Significant advances have also been made in the elucidation of signaling pathway components, resulting in the identification of novel pathways that can lead to pathologic conditions. Specific topics include mitogen-activated protein kinase , phosphatidylinositol 3-kinase , and G-protein-coupled receptor cross-talk pathways. Within this context, recent studies identifying underlying transcriptional mechanisms involved in the regulation of the α1AR subtypes is also discussed. Finally, given the potentially important role of α1ARs in the vasculature, as well as in the pathology of many diseases, such as myocardial hypertrophy and benign prostatic hyperplasia, the clinical relevance of α1AR distribution, pharmacology, and therapeutic intervention is reviewed.
    Pharmacology & Therapeutics - PHARMACOL THER. 01/2000; 88(3):281-309.
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    ABSTRACT: PurposeTo identify and quantitate alpha1-adrenergic receptor (alpha1 AR) subtype expression in human detrusor.
    Journal of Urology - J UROL. 01/1998; 160(3):937-943.
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    ABSTRACT: The β3-adrenoceptor is a G protein-coupled receptor which mediates metabolic functions of the endogenous catecholamines epinephrine and norepinephrine. Questions exist regarding distribution of the β3-adrenoceptor in human tissue. In order to examine the distribution of β3-adrenoceptor mRNA in human tissues, we used sensitive and specific RNase protection assays without previous PCR amplification in an extensive list of human tissues. We confirm the presence of β3-adrenoceptor mRNA in human white fat from several locations, gall bladder, and small intestine, as well as extend the distribution of β3-adrenoceptor mRNA to previously uncharacterized human tissues such as stomach and prostate. The presence of β3-adrenoceptor mRNA in human white adipose tissue has important implications regarding possible use of β3-adrenoceptor selective agonists as anti-obesity agents, and the demonstration of β3-adrenoceptor mRNA in a number of gastrointestinal tissues and prostate raises the question of the role of the β3-adrenoceptor in motility and secretory processes.
    European Journal of Pharmacology Molecular Pharmacology 01/1995;
  • Anesthesiology 01/1994; 81(5). · 5.16 Impact Factor