Abstract:
:Successful development and use of biomarkers will improve the productivity of oncology drug development. Recognition of the importance of biomarkers for speeding drug development is reflected in the precise definitions and concepts proposed by an NIH Working Group to standardize terminology and promote a more coherent and systematic approach to the development and use of biomarkers. Potential clinical biomarkers of drug efficacy are often identified through pre-clinical studies or basic research. Identification of potential biomarkers for use in oncology is moving rapidly forward through continuing advances in clinical imaging technologies, especially molecular and functional imaging. Other rapid advances are a product of the growing availability of new scientific reagents for established technologies and of high-throughput genomic and proteomic technologies that can generate hundreds of potential biomarkers for further evaluation. In certain cases, conventional clinical diagnostic techniques or assays can be adapted for use in pre-clinical models to evaluate their ability to serve as biomarkers for predicting clinical responses to new drug candidates. Evaluation (pre-clinical and clinical) of a potential biomarker is often the longest stage of biomarker development, and standards for evaluation or validation depend on the intended use and stage of clinical development. Biomarkers verified for use in preclinical studies can be used to help select appropriate animal models and lead compounds. Biomarkers verified for use in clinical trials can confirm a drug's pharmacological or biological mechanism of action, guide protocol design, aid patient and dose selection, and help to minimize safety risks. Oncology drug development can be optimized by using a tiered set of clinical biomarkers that predict compound efficacy and safety with increasing confidence at each rise in tier thereby aiding corporate decision-making about advancing compounds. In oncology, a special class of extensively evaluated biomarkers of efficacy (surrogate endpoints) that generally correlate with desired clinical outcomes can be used as a basis for corporate decisions as well as for gaining accelerated provisional regulatory approval of a drug.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Floyd E,McShane TMdoi
10.1080/01926230490425021subject
Has Abstractpub_date
2004-03-01 00:00:00pages
106-15eissn
0192-6233issn
1533-1601journal_volume
32 Suppl 1pub_type
杂志文章,评审abstract::Systemic hypoxemia, occurring in space-occupying lung pathologies such as inflammation and neoplasms. reduces the gas exchange area and stimulates catecholamine secretion from the adrenal medulla where chronic endocrine hyperactivity may lead to hyperplasia and neoplasia. We investigated the possible correlation betwe...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/019262302753559605
更新日期:2002-03-01 00:00:00
abstract::Carcinogenicity testing of antitumor agents in animal bioassays has been proposed because of the potential for carcinogenicity of this class of agents and the expectation that such testing may indicate prospectively the target organs of any related human oncogenesis. The literature reveals the anticipated confirmation...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262338501300305
更新日期:1985-01-01 00:00:00
abstract::The common marmoset, Callithrix jacchus, is the smallest nonhuman primate commonly used in biomedical research. Marmoset characteristics and propensities have enabled them to be used in a wide range of research as a model of human disease, physiology, drug metabolism, general toxicology, and reproductive biology. This...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/01926230390175002
更新日期:2003-01-01 00:00:00
abstract::Gadolinium is used as a contrast media for magnetic resonance imaging and, experimentally, to block Kupffer cell phagocytosis. In this study, we utilize electron probe microanalysis to determine the subcellular localization of gadolinium chloride (GdCl3) administered to mice in a short-term toxicology study. Male CD-1...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400508
更新日期:1996-09-01 00:00:00
abstract::The microbiome is increasingly recognized as a critical component in human development, health, and disease. Its relevance to toxicology and pharmacology involves challenges to current concepts related to absorption, metabolism, gene:environment, and pathways of response. Framing testable hypotheses for experimental a...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623316672073
更新日期:2017-01-01 00:00:00
abstract::Cysteamine is the first chemical identified that induces acute and chronic duodenal ulcers in rodents. Structure-activity studies with cysteamine, propionitrile and their derivatives, as well as with analogues of toluene, revealed numerous alkyl and aryl duodenal ulcerogens. Among these, one of the most interesting fr...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262338801600213
更新日期:1988-01-01 00:00:00
abstract::The lung is a target organ for the toxic effects of several chemical agents, including natural products, industrial chemicals, pesticides, environmental agents, and occasionally, drugs. Factors that establish the lung as a target organ include selective tissue exposure, high tissue oxygenation, and the presence of bio...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262339101900415
更新日期:1991-01-01 00:00:00
abstract::Our previous studies showed that protein kinase Cepsilon (PKCepsilon) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma forma...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230701748164
更新日期:2007-12-01 00:00:00
abstract::The 2015 Annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to p...
journal_title:Toxicologic pathology
pub_type:
doi:10.1177/0192623316631844
更新日期:2016-06-01 00:00:00
abstract::The outcome of cardiac ischemic events depends not only on the extent and duration of the ischemic stimulus but also on the myocardial intrinsic tolerance to ischemic injury. Cardiac ischemic tolerance reflects myocardial functional reserves that are not always used when the tissue is appropriately oxygenated. Ischemi...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623309339503
更新日期:2009-08-01 00:00:00
abstract::Biomass burning is a major source of indoor air pollution in rural India. The authors investigated in this study whether cumulative exposures to biomass smoke cause activation of the serine/threonine kinase Akt in airway cells and peripheral blood lymphocytes (PBL). For this, the authors enrolled 87 premenopausal (med...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623310385139
更新日期:2010-12-01 00:00:00
abstract::Transgenic Tg.AC mice carry a v-Ha-ras coding region flanked by a zeta-globin promoter and an SV40 polyadenylation signal sequence. These mice respond to carcinogens by developing epidermal papillomas. In some cases, malignancies develop at the sites of these papillomas. Various patterns of squamous cell differentiati...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339802600407
更新日期:1998-07-01 00:00:00
abstract::We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine t...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623314532036
更新日期:2015-02-01 00:00:00
abstract::The performance of the p53-/- transgenic (knockout) mouse model was evaluated through review of the data from 31 short-term carcinogenicity studies with 21 compounds tested as part of the International Life Sciences Institute's (ILSI) Alternatives to Carcinogenicity Testing (ACT) project, together with data from other...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/019262301753178465
更新日期:2001-01-01 00:00:00
abstract::The Syrian hamster embryo (SHE) cell-transformation assay represents a short-term in vitro assay capable of predicting rodent carcinogenicity of chemicals with a high degree of concordance (LeBoeuf et al [1996]. Mutat Res 356: 85-127). The SHE assay models the earliest identifiable stage in carcinogenicity, morphologi...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/019262301753178546
更新日期:2001-01-01 00:00:00
abstract::The two-year rodent bioassay is one of several tests that are widely used by governmental regulatory agencies as well as pharmaceutical and chemical companies to determine the carcinogenic potential of chemicals or environmental agents where human exposure is anticipated. That this assay has remained relatively unchan...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/01926230390201273
更新日期:2003-07-01 00:00:00
abstract::BMS-645737, an inhibitor of vascular endothelial growth factor (VEGF) receptor-2 and fibroblast growth factor (FGF) receptor-1, has anti-angiogenic activity and was evaluated in nonclinical studies as a treatment for cancer. This article characterizes the BMS-645737-induced clinical, gross, and histologic lesions of i...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623309357950
更新日期:2010-02-01 00:00:00
abstract::In the Federal Register of January 10, 2000 (65 FR 1399), FDA published a draft guidance entitled "Photosafety Testing." The notice gave interested persons an opportunity to submit comments. As a result of the comments, certain sections of the guidance were reworded to improve clarity. A final guidance was published i...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230490463821
更新日期:2004-07-01 00:00:00
abstract::Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339702500501
更新日期:1997-09-01 00:00:00
abstract::There is increased interest to use minipigs in ocular toxicology studies due to their anatomical similarities with human eyes and as a substitute for nonhuman primates. This requires adaptation of enhanced optical coherence tomography (OCT) techniques and of ocular relevant immunohistochemistry (IHC) or in situ hybrid...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623315615553
更新日期:2016-04-01 00:00:00
abstract::Chronic (24-month) inhalation exposure to 5 or 10 ppm allyl glycidyl ether (AGE) induced nasal lesions in Osborne-Mendel rats and B6C3F1 mice. Inflammation, degeneration, regeneration, metaplasia, hyperplasia, and neoplasia were observed in the nasal mucosa. Squamous metaplasia and hyperplasia of the respiratory epith...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339202000311
更新日期:1992-01-01 00:00:00
abstract::Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory c...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230600611752
更新日期:2006-01-01 00:00:00
abstract::We examined the localization and expression of the nuclear oncoprotein c-myc and the cytoplasmic membrane-associated oncoprotein c-ras in rainbow trout cell lines derived from both normal and tumor tissue in order to question whether c-myc and ras oncoprotein immunostaining was increased in cells derived from tumors c...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400310
更新日期:1996-05-01 00:00:00
abstract::GJA1 gene (Connexin43, also known as Cx43) is the most abundant gap junction protein isoform in animal cells and is associated with bone development in embryos. The objective of the present work was to evaluate in vivo osteal development in GJA1-deficient fetal mice through determination of the histological and molecu...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623311422075
更新日期:2011-12-01 00:00:00
abstract::Determining the carcinogenic potential of materials to which humans have significant exposures is an important, complex, and imperfect exercise. Not only are the methods for such determinations protracted and expensive and use large numbers of animals, extrapolation of data from such studies to human risk is imprecise...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623309351892
更新日期:2010-01-01 00:00:00
abstract::Sprague-Dawley CD rats received daily oral doses (45 mg/kg) of the cationic amphiphilic tricyclic antidepressant imipramine HCl (Tofranil) for up to two years. Representative specimens of liver, lung, spleen, mesenteric lymph node, retina and dorsal root ganglion were examined for myeloid bodies (MB). The extent that ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262338301100102
更新日期:1983-01-01 00:00:00
abstract::Animal models have provided an important tool to help make the decision to take potential therapies from preclinical studies to humans. In the past several years, the strong reliance of the pharmaceutical discovery and development process on the use of animal models has come under increasing scrutiny for ethical and s...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623314555162
更新日期:2015-01-01 00:00:00
abstract::Cancer affects approximately 1 in 3 individuals. An individual's susceptibility to cancer is partly determined by environmental exposures and by the combination of inherited cancer susceptibility and resistance genes. Initial mapping of these low penetrance cancer susceptibility genes has been done in the mouse becaus...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/01926230490424716
更新日期:2004-03-01 00:00:00
abstract::Alanine aminotransferase (ALT) is used as an indicator of hepatocellular injury. Since ALT consists of two isoenzymes, a better understanding of ALT isoenzyme biology in response to compounds that cause metabolic adaptive versus hepatotoxic responses will allow for a more accurate assessment of the significance of an ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623312447550
更新日期:2012-12-01 00:00:00
abstract::The evaluation of neurotoxic damage involves a unique set of challenges. Vulnerable structures, such as neocortex, hippocampus, spinal cord, and peripheral nerve are complex and sharply differentiated; deficits can result from insults to one or more element(s) in the system (e.g., myelin, axon, soma, synapse, or glia)...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623310390231
更新日期:2011-01-01 00:00:00