| Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer |
MAY 2011 |
61 pages |
| Authors:
Ivy Chung; CHILDREN'S HOSPITAL CORP BOSTON MA
|
 | 14. ABSTRACT The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a potential anti-metastatic prostate cancer therapy. We identified benzimidazoles, a class of anti-parasitic drug, in a drug screening process for preferential anti-tumor activity on metastatic prostate cancer cells. We demonstrated that benzimidazoles have potent anti-tumor activities, mediated through cell cycle arrest and induction of apoptosis. Our data indicates that benzimidazole treatment prolong the survival ... |
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| The Oncogenic Palmitoyl-Protein Network in Prostate Cancer |
31 Mar 2011 |
7 pages |
| Authors:
Michael R Freeman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Molecular studies of cancer cells and tissues have revealed that the basis for malignant tumor formation, growth, and spread is the disruption of normal patterns of gene and protein expression. Although this concept is fundamental to our understanding of cancer, genes and proteins also interact with a wide range of fat (lipid) molecules in a complex metabolic network. Studies of this lipid network have lagged considerably behind those of genetic ... |
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| Angiogenesis and Tissue Engineering Research |
Aug 2010 |
43 pages |
| Authors:
Donald Ingber; Mark Puder; Joyce Bischoff; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Centers on the development of new medical therapies and regenerative medicine approaches for the treatment of injured soldiers, and the improvement of the overall health and performance of military personnel. Over the past year we designed to develop aerosol therapies to save lives in patients with pulmonary edema and Acute Respiratory Distress Syndrome (ARDS; we evaluated the anti-malarial activity of an oral angiogenesis inhibitor developed in past grant funding periods, ... |
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| A Cholesterol-Sensitive Regulator of the Androgen Receptor |
Jul 2010 |
11 pages |
| Authors:
Michael R Freeman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Published studies from our laboratory have shown that critical mediators of tumor cell physiology and behavior reside in cholesterol-rich, lipid raft membranes of prostate cancer cells. This project focuses on the RNA binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP-K) as a novel regulator of the androgen receptor (AR). We have found that hnRNP-K lies within the cholesterol-sensitive PI3K/Akt/PTEN/mTOR pathway and that hnRNP-K connects ErbB receptor/Akt-derived signals with androgenic signals, thereby ... |
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| Membrane Heterogeneity in Akt Activation in Prostate Cancer |
01 Nov 2009 |
14 pages |
| Authors:
Martin H Hager; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project focused on the novel finding from our group that the serine-threonine kinase Akt1 partitions into specialized membrane microdomains, termed lipid rafts, and that this localization event strongly influences the nature of Akt1 signaling. Lipid rafts are cholesterol-enriched membrane microdomains that serve as signal transduction platforms by sequestering and excluding signaling proteins and by harboring multi-protein complexes. Evidence was presented in the original proposal that in prostate cancer cells ... |
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| Functional Proteomic Analysis of Lipid Raft Kinase Complexes |
Aug-2009 |
100 pages |
| Authors:
Wei Yang; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| A series of studies from our laboratories suggested that survival signaling in prostate cancer cells is mediated, in part, through lipid raftresident Akt. I have hypothesized that the lipid raft-resident Akt in prostate tumor cells is a privileged Akt population that mediates cell survival by interacting with discrete subsets of regulatory proteins and by transmitting signals that are unique to the lipid raft environment. Many components in lipid raft-resident Akt ... |
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| Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-Abdominal Adhesions, and Arterial Injuries |
Apr-2009 |
176 pages |
| Authors:
Donald Ingber; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The three goals of this project are: (i) to discover and develop novel drugs which could prevent or reverse the vascular leak syndrome; (ii) to develop angiogenesis inhibitors which would inhibit post-operative abdominal adhesions; and, (iii) to isolate endothelial progenitor cells from blood, capable of being expanded in vitro and applied to vascular grafts. Progress has been made in each category: we have made considerable progress in determining the efficacy ... |
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| Membrane Heterogeneity in Akt Activation in Prostate Cancer |
Mar 2009 |
9 pages |
| Authors:
Martin H Hager; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project focuses on the novel finding from our group that the serine-threonine kinase Akt1 partitions into specialized membrane microdomains, termed lipid rafts, and that this localization event strongly influences the nature of Akt1 signaling. Lipid rafts are cholesterol-enriched membrane microdomains that serve as signal transduction platforms by sequestering and excluding signaling proteins and by harboring multi-protein complexes. Evidence was presented in the original proposal that in prostate cancer cells ... |
|
| Exploring the Mechanisms of Pathogenesis in Prostate Cancer Involving TMPRSS2-ERG (Or ETV1) Gene Rearrangement |
Jan-2009 |
11 pages |
| Authors:
Stuart H Orkin; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Recently, gene rearrangements involving ETS family transcription factors have been identified in 50% of prostate cancer cases. To address roles of these ETS factors, especially ERG, the most frequently rearranged ETS gene in prostate cancer, as well as in normal prostate development, we planned to, 1. Generate conditional knockin mouse models of prostate cancer based on the newly identified TMPRSS2-ERG (or ETV1) gene arrangements; 2 Explore roles of Erg during ... |
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| Engineering Robust and Functional Vascular Networks in Vivo with Human Adult and Cord Blood-Derived Progenitor Cells |
Dec-2008 |
9 pages |
| Authors:
J M Melero-Martin; J Bischoff; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The success of therapeutic vascularization and tissue engineering (TE) will rely on our ability to create vascular networks using human cells that can be obtained readily, expanded safely ex vivo and produce robust vasculogenic activity in vivo. We hypothesized that blood derived endothelial progenitor cells (EPCs) have the required proliferative and vasculogenic activity to create vascular networks in vivo. To test this, EPCs were isolated and expanded from human umbilical ... |
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| Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-abdominal Adhesions, and Arterial Injuries |
01 APR 2008 |
89 pages |
| Authors:
Judah Folkman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The three goals of this project are: (i) to discover and develop novel drugs which could prevent or reverse the vascular leak syndrome; (ii) to develop angiogenesis inhibitors which would inhibit post-operative abdominal adhesions; and, (iii) to isolate endothelial progenitor cells from blood, capable of being expanded in vitro and applied to vascular grafts. Progress has been made in each category: we have demonstrated that the widely used antibiotic, doxycyline, ... |
|
| Prevention of the Angiogenic Switch in Human Breast Cancer |
MAR 2008 |
123 pages |
| Authors:
Judah Folkman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Our overall goal is to determine if human breast cancer can be prevented from becoming angiogenic when it is still at a microscopic size (< ~ 1 mm3). Some of our key research accomplishments this year are: (i) Heat shock protein-27 (HSP-27) was identified as a gene that was upregulated 27-fold in the angiogenic breast cancer cells MDA-MB-436 as compared to the non-angiogenic dormant breast cancer cells. (ii) Increased expression ... |
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| Exploring the Mechanisms of Pathogenesis in Prostate Cancer Involving TMPRSS2-ERG (Or ETV1) Gene Rearrangement |
Jan-2008 |
8 pages |
| Authors:
Stuart H Orkin; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Recently, gene rearrangements involving ETS family transcription factors have been identified in 50% of prostate cancer cases. To address roles of these ETS factors, especially ERG, the most frequently rearranged ETS gene in prostate cancer, as well as in normal prostate development, we planned to, 1. Generate conditional knockin mouse models of prostate cancer based on the newly identified TMPRSS2- ERG (or ETV1) gene arrangements; 2 Explore roles of Erg ... |
|
| Prevention of the Angiogenic Switch in Human Breast |
01 MAR 2007 |
22 pages |
| Authors:
Judah Folkman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Our overall goal is to determine if human breast cancer can be prevented from becoming angiogenic when it is still at a microscopic size (< ~ 1 mm3). To date we have made the following progress: (1) We have cloned three different human breast cancers that undergo the angiogenic switch at predictable times. (2) We have found that the angiogenic switch time is modified by host stroma: two-fold earlier for ... |
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| Mouse Model of Human Breast Cancer Initiated by a Fusion Oncogene |
SEP 2006 |
14 pages |
| Authors:
Stuart H. Orkin; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| In this study, we generated a novel mouse model of human breast cancer based on a recurrent chromosomal translocation that produces the TEL-NTRK3 fusion oncogene, as the initiating mutation in human secretory breast carcinoma. In this model, we created a Ore-lox conditional knockin allele (TN) to express the TN fusion protein from the endogenous Tel locus in a tissue-specific manner. When TN is activated in mammary glands by whey acidic ... |
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| The Calcium Channel CaT1 in Prostate Cancer Progression |
JAN 2006 |
11 pages |
| Authors:
Michael R. Freeman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project focuses on the potential role of the calcium-selective ion channel, CaT1, in prostate cancer progression. Although the physiological role of CaT1 is still poorly understood, it may be a store-operated" calcium pore, a type of channel that is known to play a role in cell growth and survival regulation. The Aims of this project are to (1) Develop specific antibodies against CaT1 and characterize its expression pattern(s) in ... |
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| Development of Peptide Inhibitors of Rehb Signaling Pathway |
Jan 2006 |
6 pages |
| Authors:
Mustafa Sahin; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| We aim to develop protein therapeutics that neutralize growth factors that activate EGF receptor family members in breast cancer. Rather than targeting receptors themselves (as do Herceptin, Iressa, etc), we propose to target the activating ligands. Our model is Argos from Drosophila, which we showed naturally inhibits EGF receptor signaling in fruit flies by inactivating the ligand. We hope to effectively humanize Argos - making it bind human EGFR ligands ... |
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| Role of ABCB5 P-Glycoprotein in Breast Cancer Multidrug Resistance |
SEP 2005 |
22 pages |
| Authors:
Markus H. Frank; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Multidrug resistance mediated by P-glycoprotein and related ATP-binding cassette (ABC) transporters is an impediment to successful cancer therapy. Here we have examined for the first time the expression of the novel ABCB5 transporter in human physiological mammary gland tissue and in a panel of human breast cancer cell lines in an initial effort to characterize whether ABCB5 might contribute to breast cancer chemoresistance. We found ABCB5 mRNA highly expressed not ... |
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| Prevention of the Angioenic Switch in Human Breast Cancer |
MAR 2005 |
26 pages |
| Authors:
Judah Folkman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The overall goal of this research is to determine if human breast cancer can be prevented from becoming angiogenic when it is still at a microscopic size of less than approximately 1 mm(sub 3). We have made the following progress during the past year: (1) We have developed models in SCID mice of four different non-angiogenic human breast cancers, and have shown that the time to the switch to the ... |
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| The Calcium Channel CaT1 in Prostate Cancer Progression |
JAN 2004 |
40 pages |
| Authors:
Michael R. Freeman; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project focuses on the potential role of the calcium-selective ion channel, CaTl, in prostate cancer progression. Although the physiological role of CaTl is still poorly understood, it may be a "store-operated" calcium pore, a type of channel that is known to play a role in cell growth and survival regulation. The Aims of this project are to (1) Develop specific antibodies against CaTl and characterize its expression pattern(s) in ... |
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| Functional Imaging of Multidrug Resistance in Breast Cancer With PET |
AUG 2003 |
17 pages |
| Authors:
Alan B. Packard; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The object of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as 99mTc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of ... |
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| Transcriptional Regulation of the Neurofibromatosis Type 1 Gene |
MAY 2003 |
24 pages |
| Authors:
Jayhong A. Chong; Magdalene M. Moran; Martin Teichmann; J. S. Kaczmarek; Robert Roeder; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The goal of this project was to understand the transcriptional regulation of the NFl gene. Specifically to further characterize TLF-mediated regulation and identify new factors that participate in the control of NFl regulation. In addition, an attempt was made to determine signaling pathways that affect NFl levels. We found that TLF(TRF2) activates a number of different genes that include the Neurofibromatosis I (NFl)gene. Overexpression of TLF increases the amount of ... |
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| Functional Imaging of Multidrug Resistance in Breast Cancer with PET |
AUG 2002 |
12 pages |
| Authors:
Alan B. Packard; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The objective of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as Tc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of ... |
|
| Functional Imaging of Multidrug Resistance in Breast Cancer with PET |
AUG 2001 |
13 pages |
| Authors:
Alan B. Packard; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The objective of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as 99mmTc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of ... |
|
| Osteopontin CD44 Interaction: A Novel Mechanism for the Selective Homing of Breast Tumor Cells into Bone |
JUN 2001 |
22 pages |
| Authors:
Samy Ashkar; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Osteopontin, a secreted phosphoprotein, is a major modulator of the motility of several cell types including macrophages, osteoclasts and tumor cells. Through its interaction with integrins and CD44v, osteopontin can induce metalloprotease, inhibit apoptosis, inhibit NO production and induce cytokine secretion. We have recently isolated a hexa peptide from osteopontin that is chemotactic to tumor cells. Antibodies raised against this peptide neutralize the chemotactic response of tumor cells to osteopontin ... |
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| Bone Factors Regulating the Osteotropism of Metastastic Breast Cancer |
OCT 2000 |
34 pages |
| Authors:
Peter V. Hauschka; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Malignant breast adenocarcinoma cells mimic osteoblasts, a critical step in their metastatic colonization and destruction of bone. CBFAl, a transcription factor responsible for normal osteoblast differentiation, is expressed inappropriately by the human breast adenocarcinoma cell line MDA-MB-23 1, and about 2-fold more strongly by a subline Ml, recovered from an osteolytic bone metastasis of MDA-MB-23 1 in a nu/nu mouse. CBFAl expression was not detected in normal breast epithelium (HMEC ... |
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| Functional Imaging of Multidrug Resistance in Breast Cancer wit PET |
AUG 2000 |
10 pages |
| Authors:
Alan Packard; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The objective of this project is the development of a PET radiopharmaceutical for the evaluation of multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer and is characterized by the increased concentration of P- glycoprotein (Pgp), a 170 kD transmembrane glycoprotein, which reduces the intracellular concentration of ... |
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| Wnt-1 Signaling in Mammary Carcinogenesis |
APR 2000 |
21 pages |
| Authors:
Xi He; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| WNT GENES ENCODE A LARGE FAMILY OF SECRETED SIGNALING MOLECULES ESSENTIAL FOR DEVELOPMENT AND ONCOGENESIS. WNT-1, THE FOUNDING MEMBER OF THE WNT GENE FAMILY, WAS INITIALLY IDENTIFIED AS AN ONCOGENE. Ectopic wnt-1 expression causes mammary tumorigenesis in mice, providing a potential model for human breast cancer. However, the cell surface receptor (or receptors) that mediates Wnt-1 signaling has not been identified, and the molecular and biochemical ... |
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| Natural History of Plexiform Neurofibromas in NF1 |
OCT 1999 |
168 pages |
| Authors:
Bruce R. Korf; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This report marks the completion of the first year of the project Natural History of Plexiform Neurofibromas in NF1'. The goals of the project are to test the utility of volumetric MRI in the measurement of plexiform neurofibromas, to use this approach to develop a body of normative data on the growth of plexiform neurofibromas, and to establish an infrastructure including radiology, statistical analysis, clinical database, tissue bank, and pathology ... |
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| Bone Factors Regulating the Osteotropism of Metastatic Breast Cancer |
OCT 1999 |
35 pages |
| Authors:
Peter V. Hauschka; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The specificity with which breast cancer metastasizes to the human skeleton is currently unexplained. In this project we have attempted to identify the critical molecular interactions and cellular processes responsible for this osteotropism (homing and metastatic growth in bone) of breast cancer. The central hypothesis is that malignant breast adenocarcinoma cells subvert the cooperative paracrine interactions between normal bone cells, endothelial cells, and the extracellular matrix in order to establish ... |
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| Identification of the Receptor of the WNT-1 Signaling Molecule |
MAY 1999 |
11 pages |
| Authors:
Raymond Habas; Xi He; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| The Wnt gene family encodes secreted signaling molecules that play important roles in mammary tumorigenesis and embryonic development Wnt-1, the founding member, was identified as an oncogene that upon ectopic expression resulted in mice mammary tumors. Delineation of the mechanisms of Wnt-1 signaling can provide insights into the molecular nature of mammary tumor formation. Recent studies suggest that the frizzled family of proteins may ... |
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| WNT-1 Signaling in Mammary Carcinogenesis |
APR 1999 |
16 pages |
| Authors:
Xi He; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| WNT genes encode a large family of secreted signaling molecules essential for development and oncogenesis. wnt-1, the founding member of the wnt gene family, was initially identified as an oncogene which, upon ectopic expression induced by viral insertion, causes mammary tumorigenesis in mice, providing a potential model for studying human breast cancer. However, the Wnt- 1 receptor, an essential component mediating Wnt- 1 function, has not ... |
|
| Bone Factors Regulating the Osteotropism of Metastatic Breast Cancer |
OCT 1998 |
24 pages |
| Authors:
Peter V. Hauschka; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project seeks to identify the critical molecular interactions and cellular processes responsible for the preferential establishment of breast cancer metastases in the human skeleton. We are testing the hypothesis that malignant breast adenocarcinoma cells subvert the cooperative paracrine interactions between normal bone cells, endothelial cells, and the extracellular matrix in order to establish metastatic foci. We have developed strong preliminary data showing mimicry of the osteoblast phenotype by invasive ... |
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| Development of New Approaches for Breast Cancer Therapy and Diagnosis Based on Angiogenesis |
OCT 96 |
13 pages |
| Authors:
Donald Ingber; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| This project focuses on angiogenesis, the growth of new blood capillaries, as a potential target for breast cancer therapy and diagnosis. Our approach is based on our past demonstration that many of the signal transducing molecules that mediate the effects of angiogenic mitogens and extracellular matrix molecules are concentrated within specialized cell adhesion sites, known as the focal adhesion complexes (FACs). Over the past year, we demonstrated that a known ... |
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| Mechanism of Action of Ribavirin on Bunyavirus Infected Cells |
01 OCT 90 |
44 pages |
| Authors:
Jean L. Patterson; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Ribavirin (1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) or Virazole is a broad-spectrum antiviral agent whose molecular mode of action remains remarkably controversial. The drug was approved by the Food and Drug Administration in 1986 for aerosol use in infants with serious infections due to respiratory syncytial virus (RS) Ribavirin is and has been under clinical investigation against a variety of viral illness, including those due to influenza virus, Lassa fever, Korean hemorrhagic fever with renal ... |
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| The Mechanism of Action of Ribavirin on Bunyavirus Infected Cells |
03 MAR 89 |
13 pages |
| Authors:
Jean L. Patterson; CHILDREN'S HOSPITAL CORP BOSTON MA
|
| Ribavirin (1-B-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) or Virazole is a broad-spectrum antiviral agent whose molecular mode of action remains remarkably controversial. The drug was approved by the Food and Drug Administration in 1986 for aerosol use in infants with serious infections due to respiratory syncytial virus (RS). Ribavirin is and has been under clinical investigation against a variety of viral illness, including those due to influenza virus, Lassa fever, Korean hemorrhagic fever with renal ... |
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Reports by Corporate Author
