21 results on '"Hillier SM"'
Search Results
2. Book reviews.
- Author
-
Black N, Romito P, Bendelow G, Leon D, Forster S, Alaszewski A, Honigsbaum F, Curtis S, Hillier SM, Annandale E, Hart JT, Skultans V, Frankenberg R, and Brannen J
- Published
- 1990
3. Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system.
- Author
-
Simon KA, Mosadegh B, Minn KT, Lockett MR, Mohammady MR, Boucher DM, Hall AB, Hillier SM, Udagawa T, Eustace BK, and Whitesides GM
- Subjects
- A549 Cells, Cell Proliferation radiation effects, Cell Survival radiation effects, Humans, Hydrogels, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lung Neoplasms metabolism, Oxygen metabolism, Paper, Radiation Tolerance, Tumor Hypoxia radiation effects, Cell Culture Techniques methods, Lung Neoplasms radiotherapy
- Abstract
This work demonstrates the application of a 3D culture system-Cells-in-Gels-in-Paper (CiGiP)-in evaluating the metabolic response of lung cancer cells to ionizing radiation. The 3D tissue-like construct-prepared by stacking multiple sheets of paper containing cell-embedded hydrogels-generates a gradient of oxygen and nutrients that decreases monotonically in the stack. Separating the layers of the stack after exposure enabled analysis of the cellular response to radiation as a function of oxygen and nutrient availability; this availability is dictated by the distance between the cells and the source of oxygenated medium. As the distance between the cells and source of oxygenated media increased, cells show increased levels of hypoxia-inducible factor 1-alpha, decreased proliferation, and reduced sensitivity to ionizing radiation. Each of these cellular responses are characteristic of cancer cells observed in solid tumors. With this setup we were able to differentiate three isogenic variants of A549 cells based on their metabolic radiosensitivity; these three variants have known differences in their metastatic behavior in vivo. This system can, therefore, capture some aspects of radiosensitivity of populations of cancer cells related to mass-transport phenomenon, carry out systematic studies of radiation response in vitro that decouple effects from migration and proliferation of cells, and regulate the exposure of oxygen to subpopulations of cells in a tissue-like construct either before or after irradiation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
4. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer.
- Author
-
Hillier SM, Maresca KP, Lu G, Merkin RD, Marquis JC, Zimmerman CN, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Acetates chemistry, Animals, Antigens, Surface, Biological Transport, Cell Line, Tumor, Chelating Agents chemistry, Glutamic Acid chemistry, Humans, Lysine chemistry, Male, Mice, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Protease Inhibitors metabolism, Protease Inhibitors pharmacokinetics, Radiochemistry, Radionuclide Imaging, Urea chemistry, Glutamate Carboxypeptidase II antagonists & inhibitors, Molecular Imaging methods, Organotechnetium Compounds chemistry, Prostatic Neoplasms diagnosis, Protease Inhibitors chemistry, Technetium
- Abstract
Unlabelled: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and small-molecule radiopharmaceuticals targeting PSMA rapidly detect the location and extent of disease. Here we evaluated preclinically 4 novel (99m)Tc-labeled small-molecule inhibitors of PSMA with the potential for clinical translation for molecular imaging of prostate cancer in humans., Methods: Four PSMA inhibitors derived from the glutamate-urea-glutamate or glutamate-urea-lysine pharmacophores conjugated to CIM or TIM chelators were radiolabeled with (99m)Tc and evaluated in vitro and in vivo., Results: High-affinity, saturable binding to PSMA on LNCaP cells was observed with Kd values of 0.64 ± 0.46 nM for (99m)Tc-MIP-1427, 1.07 ± 0.89 nM for (99m)Tc-MIP-1404, 1.75 ± 0.32 nM for (99m)Tc-MIP-1428, and 4.35 ± 0.35 nM for (99m)Tc-MIP-1405. (99m)Tc-labeled PSMA inhibitors did not bind human prostate cancer PC3 cells, which lack PSMA, demonstrating specificity, and binding was abolished with 2-(phosphonomethyl)pentanedioic acid (PMPA), a structurally unrelated PSMA inhibitor. (99m)Tc-labeled PSMA inhibitors were shown to internalize at 37 °C. Uptake in LNCaP xenografts ranged from 9.3% to 12.4% injected dose per gram at 1 h after injection and from 7.2% to 11.0% at 4 h, with tumor-to-blood ratios ranging from 29:1 to 550:1 and tumor-to-skeletal muscle ratios ranging from 31:1 to 157:1 at 4 h. (99m)Tc-MIP-1404 exhibited the best combination of high tumor uptake and rapid clearance from kidney and nontarget tissues. (99m)Tc-MIP-1404 specifically bound to PSMA in vivo as demonstrated by the absence of uptake in PC3 xenografts and by competition with PMPA. SPECT/CT imaging corroborated the tissue distribution results, demonstrating uptake only in PSMA-expressing kidney and tumor tissue and clearance through the urinary bladder., Conclusion: These (99m)Tc-labeled radiopharmaceuticals targeting PSMA may provide a SPECT molecular imaging option to assist in the initial diagnosis of prostate cancer and the management of patient care by monitoring disease progression.
- Published
- 2013
- Full Text
- View/download PDF
5. Synthesis and SAR of ⁹⁹mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates.
- Author
-
Lu G, Maresca KP, Hillier SM, Zimmerman CN, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Cell Line, Tumor, Chelating Agents chemical synthesis, Chelating Agents pharmacokinetics, Chelating Agents pharmacology, Humans, Ligands, Male, Organotechnetium Compounds chemical synthesis, Organotechnetium Compounds pharmacokinetics, Organotechnetium Compounds pharmacology, Prostatic Neoplasms metabolism, Radionuclide Imaging, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals pharmacology, Structure-Activity Relationship, Tissue Distribution, Chelating Agents chemistry, Kallikreins antagonists & inhibitors, Organotechnetium Compounds chemistry, Prostate-Specific Antigen antagonists & inhibitors, Prostatic Neoplasms diagnostic imaging, Radiopharmaceuticals chemistry, Rhenium chemistry
- Abstract
Prostate specific membrane antigen (PSMA) is recognized as an attractive molecular target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel (99m)Tc/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC(50) values ranged from 3.8 ± 2 to >2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compounds, 23b (IC(50)=4.8 ± 2.7 nM), was radiolabeled with technetium tricarbonyl ({(99m)Tc(CO)(3)}(+)) to afford the {(99m)Tc(CO)(3)}(+) complex in excellent yield and high purity. This effort has led to the identification of a diverse series of promising high affinity {(99m)Tc(CO)(3)}(+) radiolabeled PSMA inhibitors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
6. Synthesis and SAR of novel Re/99mTc-labeled benzenesulfonamide carbonic anhydrase IX inhibitors for molecular imaging of tumor hypoxia.
- Author
-
Lu G, Hillier SM, Maresca KP, Zimmerman CN, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Carbonic Anhydrase IX, Chromatography, High Pressure Liquid, Humans, Ligands, Magnetic Resonance Spectroscopy, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Benzenesulfonamides, Antigens, Neoplasm drug effects, Carbonic Anhydrase Inhibitors chemistry, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases drug effects, Radioisotopes chemistry, Rhenium chemistry, Sulfonamides chemistry
- Abstract
Carbonic anhydrase IX (CA-IX) is upregulated in cancer in response to the hypoxic tumor microenvironment, making it an attractive molecular target for the detection of hypoxic solid tumors. A series of small molecule benzenesulfonamide based CA-IX inhibitors containing novel tridentate chelates complexed with the M(CO)(3) core (M = Re or (99m)Tc) were designed and synthesized. The in vitro binding affinity of the benzenesulfonamide rhenium complexes yielded IC(50) values ranging from 3 to 116 nM in hypoxic CA-IX expressing HeLa cells. One of the most potent compounds, 3d (IC(50) = 9 nM), was radiolabeled with technetium tricarbonyl ({(99m)Tc(CO)(3)}(+)) to afford the {(99m)Tc(CO)(3)}(+) complex in excellent yield and high purity. (99m)Tc(CO)(3)-3d bound specifically to CA-IX expressing hypoxic HeLa cells. This effort led to the identification of a diverse series of promising high affinity {(99m)Tc(CO)(3)}(+) radiolabeled CA-IX inhibitors with the potential to significantly impact diagnosis, staging, and treatment selection of hypoxic solid tumors.
- Published
- 2013
- Full Text
- View/download PDF
7. Molecular imaging of human ACE-1 expression in transgenic rats.
- Author
-
Dilsizian V, Zynda TK, Petrov A, Ohshima S, Tahara N, Haider N, Donohue A, Aras O, Femia FJ, Hillier SM, Joyal JL, Wong ND, Coleman T, Babich JW, and Narula J
- Subjects
- Animals, Disease Models, Animal, Heart Failure diagnostic imaging, Heart Failure genetics, Humans, Peptidyl-Dipeptidase A genetics, Polymerase Chain Reaction, Rats, Rats, Sprague-Dawley, Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography methods, Gene Expression Regulation, Heart Failure enzymology, Myocardium enzymology, Peptidyl-Dipeptidase A biosynthesis, RNA analysis, Up-Regulation
- Abstract
Objectives: The aim of this study was to develop a molecular imaging strategy that can monitor myocardial angiotensin-converting enzyme (ACE)-1 upregulation as a function of progressive heart failure., Background: High-affinity technetium-99m-labeled lisinopril (Tc-Lis) has been shown to specifically localize in tissues that express ACE in vivo, such as the lungs. Whether Tc-Lis can also detect upregulation of ACE in the heart, by external in vivo imaging, has not been established., Methods: Twenty-one ACE-1 over-expressing transgenic (Tg) and 18 wild-type control rats were imaged using in vivo micro single-positron emission computed tomography (SPECT)-computed tomography (CT) at 10, 30, 60, and 120 min after Tc-Lis injection. A subgroup of rats received nonradiolabeled (cold) lisinopril before the Tc-Lis injection to evaluate nonspecific binding. After imaging, the rat myocardium was explanted, ex vivo images were acquired, and percent injected dose per gram gamma-well was counted, followed by an assessment of enzyme-linked immunosorbent assay-verified ACE activity and messenger ribonucleic acid expression., Results: On micro SPECT-CT, myocardial ACE-1 uptake was best visualized in Tg rats at 120 min after Tc-Lis injection. The quantitative uptake of Tc-Lis in the myocardium was 5-fold higher in mutant Tg than in control rats at each time point after tracer injection. The percent injected dose per gram uptake was 0.74 ± 0.13 in Tg myocardium at 30 min and was reduced substantially to 0.034 ± 0.003% when pre-treated with cold lisinopril (p = 0.029). Enzyme activity assay showed a >30-fold higher level of ACE-1 activity in the myocardium of Tg rats than in controls. The ACE-1 messenger ribonucleic acid was quantified, and lisinopril was found to have no effect on ACE-1 gene expression., Conclusions: The Tc-Lis binds specifically to ACE, and the activity can be localized in Tg rat hearts that over-express human ACE-1 with a signal intensity that is sufficiently high to allow external imaging. Such a molecular imaging strategy may help identify susceptibility to heart failure and may allow optimization of pharmacologic intervention., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
8. Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents.
- Author
-
Darwish A, Blacker M, Janzen N, Rathmann SM, Czorny S, Hillier SM, Joyal JL, Babich JW, and Valliant JF
- Abstract
A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than 95% RCY with (123)I. A TAAG derivative of an inhibitor of prostate-specific membrane antigen was prepared and radiolabeled with (123)I in 85% yield where biodistribution studies in LNCap prostate cancer tumor models showed rapid clearance of the agent from nontarget tissues and tumor accumulation of 20% injected dose g(-1) at 1 h. The results presented demonstrate that the TAAG group promotes minimal nonspecific binding and that labeled conjugates can achieve high tumor uptake and exquisite target-to-nontarget ratios.
- Published
- 2012
- Full Text
- View/download PDF
9. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target.
- Author
-
Fedeles BI, Zhu AY, Young KS, Hillier SM, Proffitt KD, Essigmann JM, and Croy RG
- Subjects
- Acetylcysteine pharmacology, Animals, Cell Death drug effects, DNA Adducts metabolism, Female, Free Radical Scavengers pharmacology, HeLa Cells, Humans, Male, Mice, Mice, Nude, Oxidative Stress drug effects, Oxygen Consumption drug effects, Rats, Reactive Oxygen Species metabolism, Vitamin E pharmacology, Xenograft Model Antitumor Assays methods, Aniline Mustard pharmacology, Antineoplastic Agents, Alkylating pharmacology, Electron Transport Complex I antagonists & inhibitors, Electron Transport Complex I metabolism, Mitochondria, Liver metabolism
- Abstract
The antitumor agent 11β (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11β against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11β; flow cytometry studies showed that 11β exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11β inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11β blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11β enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11β, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition and ROS generation as a new mechanism of action for 11β, which supplements conventional DNA adduct formation to promote cancer cell death.
- Published
- 2011
- Full Text
- View/download PDF
10. 123I-MIP-1072, a small-molecule inhibitor of prostate-specific membrane antigen, is effective at monitoring tumor response to taxane therapy.
- Author
-
Hillier SM, Kern AM, Maresca KP, Marquis JC, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Animals, Antigens, Surface metabolism, Antineoplastic Agents therapeutic use, Cell Count, Cell Line, Tumor, Cell Proliferation drug effects, Glutamate Carboxypeptidase II metabolism, Glutamates chemistry, Glutamates metabolism, Humans, Iodine Radioisotopes, Male, Mice, Paclitaxel therapeutic use, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Treatment Outcome, Tumor Burden drug effects, Urea chemistry, Urea metabolism, Urea pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Glutamate Carboxypeptidase II antagonists & inhibitors, Glutamates pharmacology, Paclitaxel pharmacology, Prostatic Neoplasms drug therapy, Urea analogs & derivatives
- Abstract
Unlabelled: Because traditional endpoints in oncology trials are not always applicable for metastatic prostate cancer, better ways of following response to treatment are needed. Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal human prostate epithelium and is upregulated in prostate cancer. (S)-2-(3-((S)-1-carboxy-5-((4-(123)I-iodobenzyl)amino)pentyl)ureido)pentanedioic acid, (123)I-MIP-1072, targets PSMA and was evaluated for monitoring the growth of PSMA-positive LNCaP cells in vitro and as xenografts after paclitaxel therapy., Methods: LNCaP and 22Rv1 cells were treated with paclitaxel (0-100 nM) for 48 h, after which binding of (123)I-MIP-1072 was examined. Cell number was determined by MTS assay, and PSMA expression was analyzed by Western blotting. LNCaP xenograft-bearing mice were treated with paclitaxel (6.25 mg/kg) for 3.5 cycles of 5 d on and 2 d off. Tissue distribution of (123)I-MIP-1072 was determined on days 2 and 23 from the start of paclitaxel treatment., Results: Paclitaxel (10-100 nM) inhibited LNCaP and 22Rv1 cell growth after 48 h, and binding of (123)I-MIP-1072 was proportional to cell number. Western blot analysis verified there was no paclitaxel-dependent change in PSMA expression. Treatment of LNCaP xenografts with paclitaxel resulted in a decrease in tumor volume (-21%), compared with an increase in the untreated xenografts (+205%) by day 23. Tumor uptake of (123)I-MIP-1072 was proportional to changes in tumor mass: decreased by paclitaxel treatment and increased in untreated mice., Conclusion: Treatment of LNCaP cells or xenograft tumors with paclitaxel resulted in growth inhibition, which was detected with (123)I-MIP-1072. The high specificity of (123)I-MIP-1072 for prostate cancer may allow monitoring of tumor progression in patients before, during, and after chemotherapy.
- Published
- 2011
- Full Text
- View/download PDF
11. Novel polar single amino acid chelates for technetium-99m tricarbonyl-based radiopharmaceuticals with enhanced renal clearance: application to octreotide.
- Author
-
Maresca KP, Marquis JC, Hillier SM, Lu G, Femia FJ, Zimmerman CN, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Alkylation, Amino Acids pharmacokinetics, Animals, Cell Line, Tumor, Chelating Agents pharmacokinetics, Digestive System metabolism, Digestive System pathology, Kidney Function Tests, Liver metabolism, Liver pathology, Metabolic Clearance Rate physiology, Mice, Mice, Nude, Octreotide analogs & derivatives, Octreotide chemical synthesis, Octreotide chemistry, Radiopharmaceuticals chemistry, Rats, Technetium chemistry, Time Factors, Tissue Distribution, Amino Acids chemistry, Chelating Agents chemistry, Kidney metabolism, Octreotide pharmacokinetics, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Technetium pharmacokinetics
- Abstract
Single amino acid chelate (SAAC) systems for the incorporation of the M(CO)(3) moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation Tc(CO)(3)-dipyridyl complexes has resulted in substantial hepatobiliary uptake when either examined as lysine derivatives or integrated into biologically active small molecules and peptides. Here we designed, synthesized, and evaluated novel SAAC systems that have been chemically modified to promote overall Tc(CO)(3)L(3) complex hydrophilicity with the intent of enhancing renal clearance. A series of lysine derived SAAC systems containing functionalized polar imidazole rings and/or carboxylic acids were synthesized via reductive alkylation of the epsilon amino group of lysine. The SAAC systems were radiolabeled with (99m)Tc, purified, and evaluated for radiochemical stability, lipophilicity, and tissue distribution in rats. The log P values of the (99m)Tc complexes were determined experimentally and ranged from -0.91 to -2.33. The resulting complexes were stable (>90%) for at least 24 h. Tissue distribution in normal rats of the lead (99m)Tc complexes demonstrated decreased liver (<1 %ID/g) and gastrointestinal clearance (<1.5%ID/g) and increased kidney clearance (>15 %ID/g) at 2 h after injection compared to the dipyridyl lysine complex (DpK). One of the new SAAC ligands, [(99m)Tc]bis-carboxymethylimidazole lysine, was conjugated to the N-terminus of Tyr-3 octreotide and evaluated for localization in nude mice bearing AR42J xenografts to examine tissue distribution, tumor uptake and retention, clearance, and route of excretion for comparison to (111)In-DOTA-Tyr-3-octreotide and (99m)Tc-DpK-Tyr-3-octreotide. (99m)Tc-bis-(carboxymethylimidazole)-lysine-Tyr-3-octreotide exhibited significantly less liver uptake and gastrointestinal clearance compared to (99m)Tc-DpK-Tyr-3-octreotide while maintaining tumor uptake in the same mouse model. These novel chelators demonstrate that lipophilicity can be controlled and organ distribution significantly altered, opening up broad application of these novel SAAC systems for radiopharmaceutical design.
- Published
- 2010
- Full Text
- View/download PDF
12. A qualitative study of the views of patients with long-term conditions on family doctors in Hong Kong.
- Author
-
Mercer SW, Siu JY, Hillier SM, Lam CL, Lo YY, Lam TP, and Griffiths SM
- Subjects
- Aged, Evaluation Studies as Topic, Female, Health Services Accessibility economics, Health Services Accessibility standards, Hong Kong, Humans, Interviews as Topic, Long-Term Care methods, Male, Middle Aged, Physician-Patient Relations, Physicians, Family statistics & numerical data, Practice Patterns, Physicians', Public Health, Long-Term Care psychology, Patient Satisfaction statistics & numerical data, Physicians, Family standards, Primary Health Care standards
- Abstract
Background: Primary care based management of long-term conditions (LTCs) is high on the international healthcare agenda, including the Asia-Pacific region. Hong Kong has a 'mixed economy' healthcare system with both public and private sectors with a range of types of primary care doctors. Recent Hong Kong Government policy aims to enhance the management of LTCs in primary care possibly based on a 'family doctor' model. Patients' views on this are not well documented and the aim of the present study was to explore the views of patients with LTCs on family doctors in Hong Kong., Methods: The views of patients (with a variety of LTCs) on family doctors in Hong Kong were explored. Two groups of participants were interviewed; a) those who considered themselves as having a family doctor, b) those who considered themselves as not having a family doctor (either with a regular primary care doctor but not a family doctor or with no regular primary care doctor). In-depth individual semi-structured interviews were carried out with 28 participants (10 with a family doctor, 10 with a regular doctor, and 8 with no regular doctor) and analysed using the constant comparative method., Results: Participants who did not have a family doctor were familiar with the concept but regarded it as a 'luxury item' for the rich within the private healthcare system. Those with a regular family doctor (all private) regarded having one as important to their and their family's health. Participants in both groups felt that as well as the more usual family medicine specialist or general practitioner, traditional Chinese medicine practitioners also had the potential to be family doctors. However most participants attended the public healthcare system for management of their LTCs whether they had a family doctor or not. Cost, perceived need, quality, trust, and choice were all barriers to the use of family doctors for the management of their LTCs., Conclusions: Important barriers to the adoption of a 'family doctor' model of management of LTCs exist in Hong Kong. Effective policy implementation seems unlikely unless these complex barriers are addressed.
- Published
- 2010
- Full Text
- View/download PDF
13. Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma.
- Author
-
Joyal JL, Barrett JA, Marquis JC, Chen J, Hillier SM, Maresca KP, Boyd M, Gage K, Nimmagadda S, Kronauge JF, Friebe M, Dinkelborg L, Stubbs JB, Stabin MG, Mairs R, Pomper MG, and Babich JW
- Subjects
- Animals, Drug Evaluation, Preclinical, Female, Humans, Macaca fascicularis, Male, Melanoma, Experimental diagnostic imaging, Melanoma, Experimental pathology, Mice, Mice, Nude, Neoplasm Metastasis, Radiotherapy Dosage, Survival Rate, Tomography, Emission-Computed, Single-Photon, Benzamides therapeutic use, Iodine Radioisotopes therapeutic use, Melanins metabolism, Melanoma, Experimental radiotherapy, Radiopharmaceuticals therapeutic use, Xenograft Model Antitumor Assays
- Abstract
Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma., ((c)2010 AACR.)
- Published
- 2010
- Full Text
- View/download PDF
14. Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.
- Author
-
Hillier SM, Maresca KP, Femia FJ, Marquis JC, Foss CA, Nguyen N, Zimmerman CN, Barrett JA, Eckelman WC, Pomper MG, Joyal JL, and Babich JW
- Subjects
- Animals, Antigens, Surface analysis, Cell Line, Tumor, Drug Evaluation, Preclinical, Glutamate Carboxypeptidase II analysis, Glutamates chemistry, Humans, Iodine Radioisotopes, Lysine analogs & derivatives, Lysine metabolism, Male, Mice, Mice, Nude, Neoplasm Transplantation, Prostatic Neoplasms metabolism, Protein Binding, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Urea metabolism, Antigens, Surface metabolism, Glutamate Carboxypeptidase II antagonists & inhibitors, Glutamate Carboxypeptidase II metabolism, Glutamates metabolism, Prostatic Neoplasms diagnosis, Radiopharmaceuticals metabolism, Urea analogs & derivatives
- Abstract
Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (K(i) = 4.6 +/- 1.6 nmol/L and 0.24 +/- 0.14 nmol/L, respectively) and, when radiolabeled with (123)I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (K(d) = 3.8 +/- 1.3 nmol/L and 0.81 +/- 0.39 nmol/L, respectively). The association of [(123)I]MIP-1072 and [(123)I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [(123)I]MIP-1072 and [(123)I]MIP-1095 internalized into LNCaP cells at 37 degrees C. Tissue distribution studies in mice showed 17.3 +/- 6.3% (at 1 hour) and 34.3 +/- 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [(123)I]MIP-1072 and [(123)I]MIP-1095, respectively. [(123)I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [(123)I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [(123)I]MIP-1072 and [(123)I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.
- Published
- 2009
- Full Text
- View/download PDF
15. Comprehensive radiolabeling, stability, and tissue distribution studies of technetium-99m single amino acid chelates (SAAC).
- Author
-
Maresca KP, Hillier SM, Femia FJ, Zimmerman CN, Levadala MK, Banerjee SR, Hicks J, Sundararajan C, Valliant J, Zubieta J, Eckelman WC, Joyal JL, and Babich JW
- Subjects
- Amino Acids chemistry, Animals, Chelating Agents chemistry, Intestinal Mucosa metabolism, Isotope Labeling, Kidney metabolism, Liver metabolism, Lysine analogs & derivatives, Lysine chemistry, Male, Molecular Structure, Radiopharmaceuticals chemistry, Rats, Rats, Sprague-Dawley, Stereoisomerism, Technetium chemistry, Tissue Distribution, Amino Acids pharmacokinetics, Chelating Agents pharmacokinetics, Lysine pharmacology, Radiopharmaceuticals pharmacokinetics, Technetium pharmacokinetics
- Abstract
Technetium tricarbonyl chemistry has been a subject of interest in radiopharmaceutical development over the past decade. Despite the extensive work done on developing chelates for Tc(I), a rigorous investigation of the impact of changing donor groups and labeling conditions on radiochemical yields and/or distribution has been lacking. This information is crucially important if these platforms are going to be used to develop molecular imaging probes. Previous studies on the coordination chemistry of the {M(CO)(3)}(+) core have established alkylamine, aromatic nitrogen heterocycles, and carboxylate donors as effective chelating ligands. These observations led to the design of tridentate ligands derived from the amino acid lysine. Such amino acid analogues provide a tridentate donor set for chelation to the metal and an amino acid functionality for conjugation to biomolecules. We recently developed a family of single amino acid chelates (SAAC) that serve this function and can be readily incorporated into peptides via solid-phase synthesis techniques. As part of these continuing studies, we report here on the radiolabeling with technetium-99m ((99m)Tc) and stability of a series of SAAC analogues of lysine. The complexes studied include cationic, neutral, and anionic complexes. The results of tissue distribution studies with these novel complexes in normal rats demonstrate a range of distribution in kidney, liver, and intestines.
- Published
- 2009
- Full Text
- View/download PDF
16. A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer.
- Author
-
Maresca KP, Hillier SM, Femia FJ, Keith D, Barone C, Joyal JL, Zimmerman CN, Kozikowski AP, Barrett JA, Eckelman WC, and Babich JW
- Subjects
- Antigens, Surface, Chromatography, High Pressure Liquid, Dimerization, Humans, Magnetic Resonance Spectroscopy, Male, Prostatic Neoplasms immunology, Radioligand Assay, Spectrometry, Mass, Electrospray Ionization, Spectrophotometry, Ultraviolet, Glutamate Carboxypeptidase II antagonists & inhibitors, Halogens chemistry, Prostatic Neoplasms drug therapy
- Abstract
Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-Cl, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC(50) values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC(50) values, p-I < o-I << m-I). The halogen atom had little affect on the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with (123)I and (131)I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.
- Published
- 2009
- Full Text
- View/download PDF
17. Synthesis and evaluation of a series of 99mTc(CO)3+ lisinopril complexes for in vivo imaging of angiotensin-converting enzyme expression.
- Author
-
Femia FJ, Maresca KP, Hillier SM, Zimmerman CN, Joyal JL, Barrett JA, Aras O, Dilsizian V, Eckelman WC, and Babich JW
- Subjects
- Animals, Gene Expression Profiling methods, Lisinopril chemistry, Lisinopril pharmacokinetics, Metabolic Clearance Rate, Organ Specificity, Organotechnetium Compounds chemistry, Radionuclide Imaging, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Rats, Rats, Sprague-Dawley, Tissue Distribution, Heart diagnostic imaging, Lisinopril analogs & derivatives, Myocardium enzymology, Organotechnetium Compounds pharmacokinetics, Peptidyl-Dipeptidase A metabolism
- Abstract
In animal models of cardiac disease and in human congestive heart failure, expression of angiotensin-converting enzyme (ACE) is upregulated in the failing heart and has been associated with disease progression leading to cardiac failure and fibrosis. To develop probes for imaging ACE expression, a series of di(2-pyridylmethyl)amine (D) chelates capable of binding M(CO)3+ (M = technetium, rhenium) was conjugated to lisinopril by acylation of the epsilon-amine of the lysine residue with a series of di(2-pyridylmethylamino)alkanoic acids where the distance of the chelator from the lisinopril core was investigated by varying the number of methylene spacer groups to produce di(2-pyridylmethyl)amine(Cx)lisinopril analogs: D(C4)lisinopril, D(C5)lisinopril, and D(C8)lisinopril. The inhibitory activity of each rhenium complex was evaluated in vitro against purified rabbit lung ACE and was shown to vary directly with the length of the methylene spacer: Re[D(C8)lisinopril], inhibitory concentration of 50% (IC50) = 3 nM; Re[D(C5)lisinopril], IC50 = 144 nM; and Re[D(C4)lisinopril], IC50 = 1,146 nM, as compared with lisinopril, IC50 = 4 nM. The in vivo specificity for ACE was determined by examining the biodistribution of the 99mTc-[D(C8)lisinopril] analog in rats with and without pretreatment with unlabeled lisinopril. Uptake in the lungs, a tissue that constitutively expresses ACE, was 15.2 percentage injected dose per gram at 10 min after injection and was dramatically reduced by pretreatment with lisinopril, supporting ACE-mediated binding in vivo. Planar anterior imaging analysis of 99mTc-[D(C8)lisinopril] corroborated these data. Thus, high-affinity 99mTc-labeled ACE inhibitor has been designed with potency similar to that of lisinopril and has been demonstrated to specifically localize to tissues that express ACE in vivo. This agent may be useful in monitoring ACE as a function of disease progression in relevant diseases such as heart failure.
- Published
- 2008
- Full Text
- View/download PDF
18. DNA adducts formed by a novel antitumor agent 11beta-dichloro in vitro and in vivo.
- Author
-
Hillier SM, Marquis JC, Zayas B, Wishnok JS, Liberman RG, Skipper PL, Tannenbaum SR, Essigmann JM, and Croy RG
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, DNA Adducts chemistry, Humans, Kinetics, Liver drug effects, Liver pathology, Male, Mass Spectrometry, Mice, Prostatic Neoplasms drug therapy, Spectrometry, Mass, Electrospray Ionization, Tissue Distribution, Transplantation, Heterologous, Antineoplastic Agents therapeutic use, Antineoplastic Agents toxicity, DNA Adducts drug effects, Nitrogen Mustard Compounds therapeutic use, Nitrogen Mustard Compounds toxicity, Steroids therapeutic use, Steroids toxicity
- Abstract
The multifunctional molecule 11beta-dichloro consists of a ligand for the androgen receptor linked to a bifunctional alkylating group, permitting it to create DNA adducts that bind the androgen receptor. We propose that binding of the androgen receptor to 11beta-DNA adducts acts to both shield damaged sites from repair and disrupt the expression of genes essential for growth and survival. We investigated the formation 11beta-DNA adducts in tumor xenograft and nontumor tissues in mice. Using [14C]-11beta-dichloro, we show that the molecule remains intact in blood and is widely distributed in mouse tissues after i.p. injection. Covalent 11beta-guanine adducts identified in DNA that had been allowed to react with 11beta-dichloro in vitro were also found in DNA isolated from cells in culture treated with 11beta-dichloro as well as in DNA isolated from liver and tumor tissues of mice treated with the compound. We used accelerator mass spectrometry to determine the levels of [14C]-11beta-DNA adducts in LNCaP cells treated in culture as well as in liver tissue and LNCaP xenograft tumors in treated mice. The level of DNA adducts in tumor tissue was found to be similar to that found in LNCaP cells in culture treated with 2.5 micromol/L 11beta-dichloro. Our results indicate that 11beta-dichloro has sufficient stability to enter the circulation, penetrate tissues, and form DNA adducts that are capable of binding the androgen receptor in target tissues in vivo. These data suggest the involvement of our novel mechanisms in the antitumor effects of 11beta-dichloro.
- Published
- 2006
- Full Text
- View/download PDF
19. Disruption of gene expression and induction of apoptosis in prostate cancer cells by a DNA-damaging agent tethered to an androgen receptor ligand.
- Author
-
Marquis JC, Hillier SM, Dinaut AN, Rodrigues D, Mitra K, Essigmann JM, and Croy RG
- Subjects
- Androgen Receptor Antagonists, Androgens, Animals, DNA Adducts chemistry, DNA Adducts metabolism, Estradiol pharmacology, Ligands, Male, Prostatic Neoplasms genetics, Steroids, Chlorinated pharmacology, Tumor Cells, Cultured, Apoptosis drug effects, DNA Damage drug effects, Gene Expression Regulation, Neoplastic drug effects, Intercalating Agents pharmacology, Prostatic Neoplasms pathology, Receptors, Androgen metabolism
- Abstract
The goal of our work was the design of DNA-damaging agents that disrupt both DNA repair and signaling pathways in prostate tumor cells. A DNA alkylator (N,N-bis-2-chloroethyl aniline) was linked to a steroid ligand (17beta-hyroxy-estra-Delta(4(5),9(10))-3-one) to produce a complex molecule (11beta-dichloro) that forms DNA adducts that bind the androgen receptor (AR). We speculated that DNA adducts in an AR-DNA adduct complex would be camouflaged from DNA repair proteins that would otherwise remove the adducts in prostate cancer cells. Furthermore, transcription dependent on the AR would be antagonized by AR redistribution to sites distant from AR-driven promoters. The anticancer potential of 11beta-dichloro was demonstrated against prostate cancer cells in vitro and in vivo. 11beta-dichloro induces a unique pattern of gene disruption, induces apoptosis in apoptosis-resistant cells, and shows promising anticancer activity in animals.
- Published
- 2005
- Full Text
- View/download PDF
20. Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti-cancer agents.
- Author
-
Sharma U, Marquis JC, Nicole Dinaut A, Hillier SM, Fedeles B, Rye PT, Essigmann JM, and Croy RG
- Subjects
- Aniline Compounds chemistry, Aniline Compounds pharmacology, Aniline Mustard, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Alkylating therapeutic use, Binding Sites, Breast Neoplasms metabolism, DNA Adducts metabolism, Dose-Response Relationship, Drug, Drug Design, Estradiol chemistry, Estradiol pharmacology, Evaluation Studies as Topic, Female, Humans, Receptors, Estrogen metabolism, Tumor Cells, Cultured, Aniline Compounds therapeutic use, Antineoplastic Agents, Alkylating chemical synthesis, Breast Neoplasms drug therapy, Cell Survival drug effects, Estradiol therapeutic use
- Abstract
A series of bifunctional compounds was prepared consisting of 17beta estradiol linked to a DNA damaging N,N-bis-(2-chloroethyl)aniline. The objective of our studies was to determine the characteristics of the linker that permitted both reaction with DNA and binding of the resultant covalent adducts to the estrogen receptor. Linker characteristics were pivotal determinants underlying the ability of the compounds to kill selectively breast cancer cells that express the estrogen receptor.
- Published
- 2004
- Full Text
- View/download PDF
21. A rationally designed genotoxin that selectively destroys estrogen receptor-positive breast cancer cells.
- Author
-
Mitra K, Marquis JC, Hillier SM, Rye PT, Zayas B, Lee AS, Essigmann JM, and Croy RG
- Subjects
- Aniline Mustard metabolism, Aniline Mustard pharmacology, Antineoplastic Agents, Alkylating chemical synthesis, Antineoplastic Agents, Alkylating metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, DNA Adducts metabolism, Drug Design, Estradiol metabolism, Estradiol pharmacology, Humans, Kinetics, Substrate Specificity, Tumor Cells, Cultured, Aniline Mustard analogs & derivatives, Antineoplastic Agents, Alkylating pharmacology, Breast Neoplasms drug therapy, Estradiol analogs & derivatives, Receptors, Estrogen metabolism
- Abstract
We describe a novel strategy to increase the selective toxicity of genotoxic compounds. The strategy involves the synthesis of bifunctional molecules capable of forming DNA adducts that have high affinity for specific proteins in target cells. It is proposed that the association of such proteins with damaged sites in DNA can compromise protein function and/or DNA repair resulting in increased toxicity. We describe the synthesis of a bifunctional compound consisting of an aniline mustard linked to the 7alpha position of estradiol. This novel compound can form covalent DNA adducts that have high affinity for the estrogen receptor. Breast cancer cells that express high levels of the estrogen receptor showed increased sensitivity to the cytotoxic effects of the new compound.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.