Publications by authors named "Cedo M Bagi"

20 Publications

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Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:67-77. Epub 2019 Feb 7.

Comparative Medicine, Pfizer Worldwide R&D, Groton, CT 06340, USA.

In drug discovery and development, X-ray micro-computed tomography (micro-CT) has gained increasing importance over the past decades. In recent years, micro-CT imaging of soft tissues has become popular due to the introduction of a variety of radiopaque contrast agents. More recently, nanoparticle-based ExiTron nano 12,000 has become commercially available for the nonclinical micro-CT imaging of soft tissues in rodents. Phagocytosis and accumulation of the contrast agent by Kupffer cells in the liver, as well as macrophages in the spleen, increase the soft tissue X-ray attenuation for up to 6 months. Therefore, it is essential to understand the potential toxicity of this nanomaterial in micro-CT imaging prior to its application in pharmacology and/or toxicology studies. Herein, we describe the time-course and distribution of the contrast in the liver, spleen and blood after a single intravenous injection (IV) of this nanoparticle contrast agent at 0.1 ml/mouse. Thoracic images of male adult C57BL/6 mice were acquired using a Bruker SkyScan 1276 micro-CT over a period of 29 days. The stability of X-ray attenuation enhancement in the above tissues was also tested after a single dose of Kupffer cell toxicant gadolinium chloride (GdCl) at 15 mg/kg on day 2. The liver, spleen and kidney were examined microscopically on days 15 and 29 post treatment. Serum and liver cytokines (IL-1β, IL-2, IL-6, IL-10, IL-12p70, IFN-γ, IP-10, MIP1-α, MIP1-β and TNF-α) were quantified on days 15 and 29 as indicators of a pro-inflammatory response to treatment. This study determined that there was an accumulation of amphophilic granular material in the cells of the mononuclear phagocyte system in the liver and spleen following a single dose of ExiTron nano 12,000 and a second dose of GdCl or its vehicle. However, ExiTron nano12000 contrast administration did not cause any hepatotoxicity in the liver, nor did pro-inflammatory cytokines release in the liver or serum. Similarly, there were no adverse pathologies in the spleen or kidneys. In summary, ExiTron nano12000 contrast agent-enhanced micro-CT could be used as a safe method in up to 29-day longitudinal efficacy and toxicology mouse studies for the non-invasive assessment of the liver and spleen.
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http://dx.doi.org/10.1016/j.vascn.2019.02.003DOI Listing
July 2019

Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments.

Toxicol Pathol 2018 06 16;46(4):408-420. Epub 2018 May 16.

3 Drug Safety Research and Development, Pfizer Inc., San Diego, California, USA.

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article-related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.
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http://dx.doi.org/10.1177/0192623318772501DOI Listing
June 2018

Metabolic Syndrome and Bone: Pharmacologically Induced Diabetes has Deleterious Effect on Bone in Growing Obese Rats.

Calcif Tissue Int 2018 06 1;102(6):683-694. Epub 2017 Dec 1.

Pfizer WRD, Comparative Medicine, Global Science and Technology, 100 Eastern Point Road, Groton, CT, 06340, USA.

Metabolic syndrome and osteoporosis share similar risk factors. Also, patients with diabetes have a higher risk of osteoporosis and fracture. Liver manifestations, such as non-alcoholic steatohepatitis (NASH), of metabolic syndrome are further aggravated in diabetics and often lead to liver failure. Our objective was to create a rat model of human metabolic syndrome and determine the long-term impact of early-onset T1D on bone structure and strength in obese growing rats. Male rats were given either standard chow and RO water (Controls) or a high-fat, high-cholesterol diet and sugar water containing 55% fructose and 45% glucose (HFD). A third group of rats received the HFD diet and a single dose of streptozotocin to induce type 1 diabetes (HFD/Sz). Body weight and glucose tolerance tests were conducted several times during the course of the study. Serum chemistry, liver enzymes, and biomarkers of bone metabolism were evaluated at 10 and 28 weeks. Shear wave elastography and histology were used to assess liver fibrosis. Cancellous bone structure and cortical bone geometry were evaluated by mCT and strength by the 3-point bending method. Body mass and fat accumulation was significantly higher in HFD and HFD/Sz rats compared to Controls. Rats in both the HFD and HFD/Sz groups developed NASH, although the change was more severe in diabetic rats. Although both groups of obese rats had larger bones, their cancellous structure and cortical thickness were reduced, resulting in diminished strength that was further aggravated by diabetes. The HFD and HFD/Sz rats recapitulate MeSy in humans with liver pathology consistent with NASH. Our data provide strong indication that obesity accompanied by type 1 diabetes significantly aggravates comorbidities of MeSy, including the development of osteopenia and weaker bones. The juvenile rat skeleton seems to be more vulnerable to damage imposed by obesity and diabetes and may offer a model to inform the underlying pathology associated with the unusually high fracture rates in obese adults with diabetes.
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http://dx.doi.org/10.1007/s00223-017-0367-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956015PMC
June 2018

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

J Bone Miner Res 2017 Oct 25;32(10):2062-2073. Epub 2017 Aug 25.

Center for Therapeutic Innovation, Pfizer, New York, NY, USA.

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816679PMC
October 2017

Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model.

Ann Rheum Dis 2017 Jan 5;76(1):295-302. Epub 2016 Jul 5.

Pfizer Inc, San Diego, California, USA.

Objective: To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials.

Methods: Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing.

Results: Gait deficiency in untreated rats was present 3-7 days after MMT surgery, with a return to normal weight-bearing by days 14-28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3-8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats.

Conclusions: These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.
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http://dx.doi.org/10.1136/annrheumdis-2015-208913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264211PMC
January 2017

Effect of antiresorptive and anabolic bone therapy on development of osteoarthritis in a posttraumatic rat model of OA.

Arthritis Res Ther 2015 Nov 6;17:315. Epub 2015 Nov 6.

Comparative Medicine, Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA.

Introduction: Osteoarthritis (OA) is a leading cause of disability, but despite the high unmet clinical need and extensive research seeking dependable therapeutic interventions, no proven disease-modifying treatment for OA is currently available. Due to the close interaction and interplay between the articular cartilage and the subchondral bone plate, it has been hypothesized that antiresorptive drugs can also reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate, prevent osteophyte formation, and/or that bone anabolic drugs might also stimulate cartilage synthesis by chondrocytes and preserve cartilage integrity. The benefit of intensive zoledronate (Zol) and parathyroid hormone (PTH) therapy for bone and cartilage metabolism was evaluated in a rat model of OA.

Methods: Medial meniscectomy (MM) was used to induce OA in male Lewis rats. Therapy with Zol and human PTH was initiated immediately after surgery. A dynamic weight-bearing (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs. At the end of the 10-week study, the rats were euthanized and the cartilage pathology was evaluated by contrast (Hexabrix)-enhanced μCT imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization.

Results: The results of this study highlight the complex changes in bone metabolism in different bone compartments influenced by local factors, including inflammation, pain and mechanical loads. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by contrast-enhanced μCT and histology. The study results showed the negative impact of MM surgery on the weight-bearing capacity of the operated limb, which was not corrected by treatment. Although both Zol and PTH improved subchondral bone mass and Zol reduced serum CTX-II level, both treatments failed to prevent or correct cartilage deterioration, osteophyte formation and mechanical incapacity.

Conclusions: The various methods utilized in this study showed that aggressive treatment with Zol and PTH did not have the capacity to prevent or correct the deterioration of the hyaline cartilage, thickening of the subchondral bone plate, osteophyte formation or the mechanical incapacity of the osteoarthritic knee.
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http://dx.doi.org/10.1186/s13075-015-0829-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635572PMC
November 2015

Correlation between μCT imaging, histology and functional capacity of the osteoarthritic knee in the rat model of osteoarthritis.

J Transl Med 2015 Aug 25;13:276. Epub 2015 Aug 25.

Pfizer Global Research & Development, Global Science & Technology, 100 Eastern Point Road MS 8274-1359, Groton, CT, 06340, USA.

Background: To acquire the most meaningful understanding of human arthritis, it is essential to select the disease model and methodology translatable to human conditions. The primary objective of this study was to evaluate a number of analytic techniques and biomarkers for their ability to accurately gauge bone and cartilage morphology and metabolism in the medial meniscal tear (MMT) model of osteoarthritis (OA).

Methods: MMT surgery was performed in rats to induce OA. A dynamic weight bearing system (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs in rats. At the end of a 10-week study cartilage pathology was evaluated by micro computed tomography (μCT), contrast enhanced μCT (EPIC μCT) imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization.

Results: The study results showed a negative impact of MMT surgery on the weight-bearing capacity of the operated limb. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by elevated CTX-II in serum, EPIC μCT and histology. Bone analysis by μCT showed thickening of the subchondral bone beneath the damaged cartilage, loss of cancellous bone at the metaphysis and active osteophyte formation.

Conclusions: The study emphasizes the need for using various methodologies that complement each other to provide a comprehensive understanding of the pathophysiology of OA at the organ, tissue and cellular levels. Results from this study suggest that use of histology, μCT and EPIC μCT, and functional DWB tests provide powerful combination to fully assess the key aspects of OA and enhance data interpretation.
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http://dx.doi.org/10.1186/s12967-015-0641-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549091PMC
August 2015

Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.

Toxicol Pathol 2015 Apr 20;43(3):411-23. Epub 2014 Aug 20.

Pfizer, Worldwide Research & Development, Cambridge, Massachusetts, USA.

Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.
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http://dx.doi.org/10.1177/0192623314546559DOI Listing
April 2015

The rational use of animal models in the evaluation of novel bone regenerative therapies.

Bone 2015 Jan 13;70:73-86. Epub 2014 Jul 13.

University of Zagreb School of Medicine, Center for Translational and Clinical Research, Laboratory for Mineralized Tissues, Salata 11, Zagreb, Croatia. Electronic address:

Bone has a high potential for endogenous self-repair. However, due to population aging, human diseases with impaired bone regeneration are on the rise. Current strategies to facilitate bone healing include various biomolecules, cellular therapies, biomaterials and different combinations of these. Animal models for testing novel regenerative therapies remain the gold standard in pre-clinical phases of drug discovery and development. Despite improvements in animal experimentation, excessive poorly designed animal studies with inappropriate endpoints and inaccurate conclusions are being conducted. In this review, we discuss animal models, procedures, methods and technologies used in bone repair studies with the aim to assist investigators in planning and performing scientifically sound experiments that respect the wellbeing of animals. In the process of designing an animal study for bone repair investigators should consider: skeletal characteristics of the selected animal species; a suitable animal model that mimics the intended clinical indication; an appropriate assessment plan with validated methods, markers, timing, endpoints and scoring systems; relevant dosing and statistically pre-justified sample sizes and evaluation methods; synchronization of the study with regulatory requirements and additional evaluations specific to cell-based approaches. This article is part of a Special Issue entitled "Stem Cells and Bone".
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http://dx.doi.org/10.1016/j.bone.2014.07.010DOI Listing
January 2015

Patient-derived xenografts reveal limits to PI3K/mTOR- and MEK-mediated inhibition of bladder cancer.

Cancer Chemother Pharmacol 2014 Mar 19;73(3):525-38. Epub 2014 Jan 19.

Comparative Medicine, Groton, CT, USA,

Background: Metastatic bladder cancer is a serious condition with a 5-year survival rate of approximately 14 %, a rate that has remained unchanged for almost three decades. Thus, there is a profound need to identify the driving mutations for these aggressive tumors to better determine appropriate treatments. Mutational analyses of clinical samples suggest that mutations in either the phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) or RAS/MEK/ERK pathways drive bladder cancer progression, although it remains to be tested whether the inhibition of either (or both) of these pathways can arrest PI3K/mTOR- or Ras-driven proliferation.

Methods: Herein, we used several bladder cancer cell lines to determine drug sensitivity according to genetic background and also studied mouse models of engrafted UM-UC-3 cells and patient-derived xenografts (PDXs) to test PI3K/mTOR and MEK inhibition in vivo.

Results: Inhibition of these pathways utilizing PF-04691502, a PI3K and mTOR inhibitor, and PD-0325901, a MEK inhibitor, slowed the tumor growth of PDX models of bladder cancer. The growth inhibitory effect of combination therapy was similar to that of the clinical maximum dose of cisplatin; mechanistically, this appeared to predominantly occur via drug-induced cytostatic growth inhibition as well as diminished vascular endothelial growth factor secretion in the tumor models. Kinase arrays of tumors harvested after treatment demonstrated activated p53 and Axl as well as STAT1 and STAT3.

Conclusion: Taken together, these results indicate that clinically relevant doses of PF-04691502 and PD-0325901 can suppress bladder tumor growth in PDX models, thus offering additional potential treatment options by a precision medicine approach.
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http://dx.doi.org/10.1007/s00280-014-2376-1DOI Listing
March 2014

Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery.

Comp Med 2011 Feb;61(1):76-85

Global Science & Technology, WWCM, Pfizer, Groton, Connecticut, USA.

To accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates. This work enhances our understanding of bone gross and microanatomy across lab animal species and likely will enable scientists to select the most appropriate species and relevant bone sites for research involving skeleton. We evaluated the gross and microanatomy of the femora head and neck, lumbar spine, and mandible and parameters of cancellous bone, including trabecular number, thickness, plate separation, and connectivity among species. The skeletal characteristics of rabbits, including a very short femoral neck and small amounts of cancellous bone at the femoral neck, vertebral body, and mandible, seem to make this species the least desirable for preclinical research of human bone physiology; in comparison, nonhuman primates seem the most applicable for extrapolation of data to humans. However, rodent (particularly rat) models are extremely useful for conducting basic research involving the skeleton and represent reliable and affordable alternatives to dogs and nonhuman primates. Radiology and microcomputed tomography allow for reliable evaluation of bone morphology, microarchitecture, and bone mineral density in preclinical and clinical environments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060425PMC
February 2011

Models of hepatocellular carcinoma and biomarker strategy.

Cancers (Basel) 2010 Jul 7;2(3):1441-52. Epub 2010 Jul 7.

Global Science & Technology, PGRD, Pfizer Inc, Groton, CT 06340, USA.

The overwhelming need to improve preclinical models in oncology has stimulated research efforts to refine and validate robust orthotopic models that closely mimic the disease population and therefore have the potential to better predict clinical outcome with novel therapies. Sophisticated technologies including bioluminescence, contrast enhanced ultrasound imaging, positron emission tomography, computed tomography and magnetic resonance imaging have been added to existing serum- and histology-based biomarkers to assist with patient selection and the design of clinical trials. The rationale for the use of human hepatocellular carcinoma (HCC) cell lines, implementation of xenograft and orthotopic animal models and utilization of available biomarkers have been discussed, providing guidelines to facilitate preclinical research for the development of treatments for HCC patients.
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http://dx.doi.org/10.3390/cancers2031441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837316PMC
July 2010

Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model.

Cancer Biol Ther 2009 May;8(9):856-65

Global Science & Technology, PGRD, Pfizer, Inc., Groton, CT 06340, USA.

Experimental Design: To investigate the antitumor effect of sunitinib and FAK/Pyk2 tyrosine kinase inhibitor (PF-562,271)combination therapy in vivo, utilizing human hepatocellular carcinoma (HCC) cells Huh7.5. Nude rats were inoculated subcutaneously with Huh7.5 hepatoma cells. Dosing for Phase 1 was initiated on day 5 post tumor inoculations with Vehicle(Group 1), sunitinib (25 mg/kg/day; Group 2) and sunitinib plus PF-562,271 combination (15 mg/kg/day; Group 3). Phase 2 of the study started on day 26, and each of the three original groups was divided in two subgroups; half of the rats remained on original therapy (Groups 1A and 2A) with the exception of Group 3A that was euthanized after Phase 1. The other half of the rats were switched to sunitinib and PF-562,271 combination (Group 1B) or vehicle (Groups 2B and 3B). Tumor volume and weight, serum alpha feto-protein (AFP), contrast-enhanced ultrasound imaging (CEUS) and tumor histology were used to evaluate effects of treatment on tumor growth.

Results: The results from this study indicate that the combination of sunitinib and PF-562,271 TKI has the potential to target different aspects of angiogenesis and tumor aggressiveness and may have significantly greater effect than relevant single agent, blocking not only tumor growth, but also impacting the ability of the tumor to recover upon withdrawal of the therapy.
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http://dx.doi.org/10.4161/cbt.8.9.8246DOI Listing
May 2009

Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases.

Cancer 2008 May;112(10):2313-21

Pfizer Inc., PGRD, World Wide Comparative Medicine, Groton, Connecticut 06340, USA.

Background: Lytic bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer.

Methods: The efficacy of PF-562,271 was evaluated using MDA-MB-231 cells implanted in the tibia of nude rats. The drug was administered orally at a dose of 5 mg/kg, 7 days per week for 28 days. Serum and urine biomarkers, imaging, and histologic techniques were deployed to monitor tumor take rate, disease progression, and response to therapy.

Results: The compound was well tolerated. Both compound-treated groups demonstrated significant and similar increases in osteocalcin and cancellous bone parameters. Radiographic evaluation of tumor-bearing tibiae revealed tumor expansion in nontreated rats compared with a decrease in tumor growth and signs of bone healing in rats treated with PF-562,271. Tartrate-resistant acid phosphatase and fluorescent in situ hybridization analysis revealed that the majority of bone resorption at the tumor site was performed by osteoclasts of rat origin.

Conclusions: The oral administration of PF-562,271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor-induced bone loss. The unique ability of PF-562,271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer-associated osteoporosis.
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http://dx.doi.org/10.1002/cncr.23429DOI Listing
May 2008

Age-related changes in marmoset trabecular and cortical bone and response to alendronate therapy resemble human bone physiology and architecture.

Anat Rec (Hoboken) 2007 Aug;290(8):1005-16

Comparative Medicine, PGRD, Pfizer Inc., Groton, Connecticut 06340, USA.

In older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, non rodent, remodeling species. This study investigated the skeletal characteristics of senescent marmosets to evaluate their suitability as an osteoporosis model. Animals were randomized across three experimental groups; controls for both sexes and marmosets receiving alendronate for either 30 or 60 days (28 microg/kg, sc, twice per week). Outcome measures included serum chemistry and bone biomarkers, DEXA, histomorphometry, micro-computed tomography, and histopathology. Results showed that the adult marmoset skeleton has similar anatomical characteristics to the adult human, including the absence of growth plates, presence of Haversian system, and true remodeling of cancellous and cortical bone. Structural analyses of senescent marmoset cancellous bone demonstrated loss of trabecular mass and architecture similar to skeletal changes described for elderly men and women. Treatment with alendronate improved trabecular volume and number by reducing bone resorption, although bone formation was also reduced through coupling of bone remodeling. The common marmoset may provide a valuable model for research paradigms targeting human bone pathology and osteoporosis due to skeletal features that are similar to age-related changes and response to bisphosphonate therapy reported for humans.
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http://dx.doi.org/10.1002/ar.20561DOI Listing
August 2007

4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17beta-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate.

Bioorg Med Chem Lett 2006 Sep 27;16(18):4965-8. Epub 2006 Jun 27.

Bayer Research Center, Bayer HealthCare, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT 06516, USA.

A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.041DOI Listing
September 2006

The use of micro-CT to evaluate cortical bone geometry and strength in nude rats: correlation with mechanical testing, pQCT and DXA.

Bone 2006 Jan 18;38(1):136-44. Epub 2005 Nov 18.

Comparative Physiology and Medicine, Safety Sciences, Pfizer Inc, Eastern Point Road 8274-1312, Groton, CT 06340, USA.

In both clinical and experimental settings, access to quantitative methods enabling the objective evaluation of cortical bone mass, structure, geometry and strength are essential for the assessment of efficacy and safety of different treatments aimed to improve bone strength. The ability of non-invasive methodologies (DXA, pQCT and micro-CT) to assess and quantify cortical bone mass and geometry was tested in a nude rat model in which bone loss was induced by surgical castration. Treatment with a bone antiresorptive (alendronate) or a bone forming (PTH) drug was used to: (A) validate the nude rat model in terms of bone metabolism, (B) test the ability of each technology to detect change in cortical bone geometry and (C) correlate cortical bone geometry with bone strength data obtained by 3-point bending method. Our observations regarding effect of castration and treatment with PTH and alendronate on cortical bone parameters in nude rats is in general agreement with previously published data obtained in immunocompetent male rats under similar experimental conditions. Data presented here support the hypothesis that nude rats have similar bone physiology and response to known bone therapies to that observed in normal rats and therefore could be effectively used to predict skeletal response in humans. All three technologies deployed in this study (DXA, pQCT and micro-CT) proved useful in describing cancellous and/or cortical bone parameters and positive correlations were demonstrated between data obtained by different methods. The cross-sectional area of a bone structure is crucial for resisting loads in bending or torsion and is described as "areal moment of inertia" for bending, and as "polar moment of inertia" in torsion. Novel, three-dimensional micro-CT methodology used in this study to assess geometry of cortical bone provides data that accurately describes cortical bone geometry and parallels cortical bone strength results obtained by the 3-point bending method. Our micro-CT data meet the criteria of providing quick, reproducible and accurate answers regarding cortical bone geometry as a predictor of cortical bone strength.
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http://dx.doi.org/10.1016/j.bone.2005.07.028DOI Listing
January 2006

Targeting of therapeutic agents to bone to treat metastatic cancer.

Authors:
Cedo M Bagi

Adv Drug Deliv Rev 2005 May 13;57(7):995-1010. Epub 2005 Apr 13.

Pfizer Inc, Global Research and Development, Safety Sciences Groton, Eastern Point Road 8274-1312, Groton, CT 06340, USA.

The three main organs affected by metastasis of all cancers include lungs, liver, and bone. Clinical confirmation of tumor spread to these organs is a negative prognostic sign that marks the stage when disease is rarely curable. Today, treatment of bone metastases is primarily palliative. The aims of treatment are to relieve pain, prevent development of pathologic fractures, improve mobility and function, and if possible, prolong survival. Significant improvements in our understanding of tumor biology along with early tumor detection has led to the discovery of few innovative approaches aimed to treat bone metastases. The most promising treatment modalities include combination of anti-cancer therapies (surgery, radiation therapy, citostatic therapy) with bone antiresorptive therapies (bisphosphonate) that specifically target osteoclasts, bone resorbing cells. The osteoclast, whose increased activity is induced by the tumor, is responsible for the deterioration of bone mass and structure along with the release of grow factors that feed back and support further tumor growth. The current pharmaceutical approach is to target bone metastases by developing drugs that specifically target tumor cells in bone in addition to bone stroma since skeletal metastases are more resistant to treatment, present the highest bulk of tumor mass in the body, serve as site for secondary spread of tumor cells, and are associated with significant morbidity. There is a real need for a more effective modified release of newer anti-cancer drugs such as gene therapy and immunotherapy by using established and novel delivery platforms that will improve therapy and reduce side effects as a result of more appropriate plasma profiles. Overall, however, developments regarding treatment of cancer metastases to bone are encouraging. The scope of future advancements is immense and includes innovative therapeutics and delivery systems aimed to improve skeletal affinity, selectivity, and efficacy of drugs.
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http://dx.doi.org/10.1016/j.addr.2004.12.014DOI Listing
May 2005

HMG-CoA reductase inhibitors - a review of the recent patent literature.

Authors:
Cedo M Bagi

IDrugs 2002 Mar;5(3):266-77

Pfizer Inc, Eastern Point Road 8274-1312, Groton, CT 06340, USA.

Statins are very potent inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis at the mevalonate level. Today there is an increasing tendency to treat hypercholesterolemia aggressively, hence, the greater use of statins worldwide. The pleiotropic effect of statins is well documented. Examination of the patent literature reveals that in the past year pharmaceutical companies continued to be very active in this area. Accumulated knowledge of the actions of statins shows that they may be involved in many more processes than originally anticipated. Hence, in addition to 'old' indications (hypercholesterolemia, hyperlipidemia and atherosclerosis) many patent applications published in 2001 attempted to cover combination therapies, widening indications for statins to almost all known diseases. Many of the 'new' claims are not well substantiated and biological data are absent. Based on the magnitude of cardiovascular disease and aging population globally this area of drug discovery will continue to be an important area of research for all pharmaceutical companies.
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March 2002

Alternative approach to assessment of bone quality using micro-computed tomography.

Bone 2004 Jul;35(1):326-33

Comparative Physiology and Medicine, Safety Sciences, Pfizer Inc., Groton, CT 06340, USA.

Micro-computed tomography (micro-CT) allows for classical anatomical imaging well suited to the study of skeletal structures. Recent improvements in spatial resolution and the ability to assess cancellous bone microstructure more efficiently has led to an increase in the number of micro-CT users in both academic and commercial environments. Accurate and reproducible positioning of bone samples and image acquisition time are two limiting factors that every bio-imaging laboratory must deal with. Therefore, method improvements that may save time or improve quality and reproducibility of data are always welcome. Here, we present an "alternative" approach for performing two- (2D) and three-dimensional (3D) analysis of bone tissue using in vitro micro-CT technology. The proposed method for acquiring longitudinal images of long bones has several advantages over the "conventional" scanning method of generating axial images. The proposed method allows for more accurate and reproducible positioning of specimen for single and multi-sample scans while providing higher-resolution image sets in substantially less time, compared to the "conventional" method. In addition, longitudinal images generated with the proposed method are comparable to views obtained by classic bone histology and, thus, are more informative to bone scientists, providing an opportunity to assess cancellous bone of the metaphysis and/or epiphysis, evaluate longitudinal bone growth, and finally to more accurately and reproducibly define regions of interest on image.
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http://dx.doi.org/10.1016/j.bone.2004.02.019DOI Listing
July 2004
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