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Vernon E Steele - One of the best experts on this subject based on the ideXlab platform.

  • abstract 2626 metabolic profiles and potential pharmacodynamic biomarkers in female sprague dawley rats on a standard 4 fat or western 20 fat diet and treated with known active or inactive Chemopreventive Agents
    Cancer Research, 2016
    Co-Authors: Matthew D Thompson, Vernon E Steele, Clinton J Grubbs, Fariba Moeinpour, Mark Steven Miller, Edward D Karoly, Ronald A Lubet
    Abstract:

    Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA The methylnitrosourea (MNU) - induced model of ER+ mammary cancers in female Sprague-Dawley rats has been routinely used in our laboratories for screening Chemopreventive Agents. In this study, we evaluated multiple known effective [tamoxifen, Targretin (an RXR agonist), Iressa (EGFR1 inhibitor)] or ineffective Agents (Lipitor, metformin) in rats placed on either standard diet (20% fat) or a Western diet (20% fat, low calcium) at 43 days of age (DOA). Rats were given MNU at 50 DOA and administered the various Agents or vehicle beginning at 57 DOA until the end of the study. Palpation of the rats showed that Agents yielded the same results in rats on either diets. Somewhat surprisingly, metformin was ineffective in rats on either diet; confirming our lack of efficacy in a standard diet (Thompson, et al, Cancer Prev Res., 2015). To look for potential pharmacodynamics biomarkers, serum was obtained from the various groups at 78 days of age and at sacrifice; when a large tumor burden was observed in rats given vehicle, Lipitor, or metformin. Levels of approximately 500 metabolites were compared in the serum (Metabolon Research, Research Triangle Park, NC). We initially looked for metabolite changes related to different diets and found differential expression of alpha 10-undecanoate, 13-methylmyristic acid, 4-hydrox-benzoate, 2-amino-heptanpate, tocopherol and nicotinamide when comparing serum from rats on Western vs standard diets. Interestingly, each of the highly effective Agents (tamoxifen, Targretin, and Iressa) yielded metabolic profiles that were strikingly different from rats given vehicle; based on unsupervised analysis. These metabolites become potential pharmacodynamic biomarkers for the highly effective doses of these Agents. In contrast, the two negative Agents did not yield a similar dichotomy between treated and vehicle serum. One could determine, however, metabolites which differed between metformin or Lipitor treated rats vs vehicle treated rats when performing a supervised analysis. We also compared serum for the early and late time points with either diet since the latter serum was from animals with a significant number of mammary cancers. We observed a number of metabolite changes including 4-OH butyrate, acetyl carnitine, oxalate, and threonate. These cancer related profiles will be discussed at greater length; in addition to the altered profiles caused by the administration of the various Chemopreventive Agents. Supported by NCI contract HHSN261201200021I. Citation Format: Matthew D. Thompson, Clinton J. Grubbs, Vernon E. Steele, Mark S. Miller, Fariba Moeinpour, Edward D. Karoly, Ronald A. Lubet. Metabolic profiles and potential pharmacodynamic biomarkers in female Sprague-Dawley rats on a standard (4% fat) or Western (20% fat) diet and treated with known active or inactive Chemopreventive Agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2626.

  • abstract 837 reproducibility of efficacy results for Chemopreventive Agents in the methylnitrosourea induced rat mammary cancer model
    Cancer Research, 2016
    Co-Authors: Vernon E Steele, Ronald A Lubet, Clinton J Grubbs
    Abstract:

    Perhaps the greatest question in biological science is: Can results be reproduced? This problem is of particular concern for a group whose primary mission is to screen for potentially effective Agents and rank results by activity. The reproducibility of testing specific Agents for Chemopreventive activity, testing the same agent in various protocols, and testing multiple Agents of a given mechanistic class in the MNU-induced model of ER+ breast cancer in Sprague-Dawley rats is presented. The model employs female virgin Sprague-Dawley rats on a standard 4% Teklad diet which develop ER+ mammary cancers (adenocarcinomas) following MNU injection at 50 days of age (DOA). Preventive Agents were given by gavage or diet starting at 55 DOA, and animals monitored for tumor development until approximately 170 DOA. Seven Agents which we had previously studied and which were strongly positive [tamoxifen, vorozole (an aromatase inhibitor), Targretin, gefitinib] or strongly negative (naproxen, Lipitor, metformin) were examined in the assays presented. These study results confirmed our previous data. We next tested these same Agents in animals given a Western diet (high fat, low calcium) and again obtained the same results. We had thought that the altered physiology and potentially altered pharmacokinetics of rats on a Western diet might alter the observed Chemopreventive efficacy. These studies show that the direct repetition of clearly positive and negative Agents can be achieved and, in fact, repeated with a significant variation in diet. Importantly, in terms of reproducibility, we find that multiple Agents of the same mechanistic class give similar results. Thus, various SERMs (tamoxifen, toremifene, Arzoxifene), RXR agonists (targretin, UAB-30, 4Me-UAB-30), EGFR inhibitors (gefitinib, Erlotinib, lapatinib) are all highly positive (70-95% reduction of cancer multiplicity). In contrast, the negative classes COX inhibitors (naproxen, sulindac, aspirin) or statins (atorvastatin or simvastatin) have been consistently negative ( Citation Format: Vernon E. Steele, Ronald A. Lubet, Clinton J. Grubbs. Reproducibility of efficacy results for Chemopreventive Agents in the methylnitrosourea-induced rat mammary cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 837.

  • abstract b53 predicting efficacy of Chemopreventive Agents in animal tumor assays by statistical modeling
    Cancer Prevention Research, 2015
    Co-Authors: Barbara K Dunn, Vernon E Steele, Richard M Fagerstrom, Carol F Topp, David F Ransohoff, Leslie G Ford, Barnett S Kramer
    Abstract:

    NCI9s Division of Cancer Prevention has over 25 years entered some 800 Agents into a program designed to test cancer preventive efficacy. Early in the testing pathway are 2 sequential critical steps: (1) in vitro/in vivo morphologic assays and, (2) for Agents successful in step 1, cancer-preventive testing (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate intention is to follow successful testing in animals with entry into clinical trial testing in humans. To facilitate the optimal selection of appropriate morphologic tests for specific disease-site animal tumor models, we undertook the current project. We evaluated the success of our strategy by determining how accurately the earlier stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. Focusing on 210 Agents that were tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the 6 most commonly used morphologic assays predicted drug efficacy in animal tumor models. Using multimodel inference, three statistical models were generated to evaluate the ability of these 6 morphologic assays to predict tumor outcomes in 3 different sets of animal tumor assays: (1) all tumor types, (2) breast cancer only, and (3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the 3 different sets of animal tumor assays. The goal is to use predictive models such as these to guide our future decision-making with respect to selection of preventive Agents as well as morphologic and animal tumor assays. In this manner, we hope to improve the efficiency of our overall approach to chemoprevention agent development. Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, David Ransohoff, Leslie G. Ford, Barnett S. Kramer. Predicting efficacy of Chemopreventive Agents in animal tumor assays by statistical modeling. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B53.

  • abstract p5 11 01 correlation of the effects of potential and known Chemopreventive Agents on proliferation rates in normal mammary glands and mammary cancers with their Chemopreventive efficacy
    Cancer Research, 2015
    Co-Authors: Brandy M Heckmanstoddard, Vernon E Steele, Clinton J Grubbs, Fariba Moeinpour, Ronald A Lubet
    Abstract:

    Core needle biopsy, fine needle aspiration, or imaging (e.g., mammography) are currently used to examine Chemopreventive agent efficacy in Phase II breast cancer trials. However, biomarker endpoints, such as proliferation rates using Ki67 in normal or "at risk" breast tissue, have not been formally validated relative to cancer outcome. The aim of this study was to validate Ki-67 in "normal" mammary tissue from the methylnitrosourea (MNU) rat mammary tumor model with mammary cancer multiplicity within the same animal as surrogate biomarker for agent efficacy. Multiple studies were performed in female Sprague-Dawley rats to correlate this proliferation biomarker in mammary tissue after two weeks of chemoprevention agent treatment with mammary cancer incidence and multiplicity at the end of the study. In brief, MNU was given at 50 days of age, one week later administration of the agent was started, and after two weeks a biopsy of the mammary gland was taken. Treatment with the Agents continued for approximately 150 days, at which time the study was terminated and mammary tumor multiplicity was measured. Changes in proliferation and mammary tumor multiplicity were compared to a control group of untreated group of animals within the same experiment using a two-sided Student t-test. In general, highly effective Agents to preventing cancers (e.g., tamoxifen) also prevented normal mammary gland proliferation after only two weeks of treatment, while inactive Agents (e.g., naproxen) had minimal effects on normal gland proliferation. The effects of the Agents on established mammary cancers (in which the Agents were given for 7 days to rats bearing small MNU-induced mammary cancers) showed similar correlations. Additional biomarkers, as well as the proliferation change and efficacy of these Agents in rats fed a high-fat (Western) diet, will also be presented. In conclusion, determining the effect of a potential Chemopreventive agent on cell proliferation following short-term treatment appears to be an effective method for predicting its efficacy in preventing mammary cancers. These data further confirm that Ki67 measurements are useful in Phase II prevention trials as a biomarker of agent efficacy. Citation Format: Brandy M Heckman-Stoddard, Clinton J Grubbs, Fariba Moeinpour, Vernon E Steele, Ronald A Lubet. Correlation of the effects of potential and known Chemopreventive Agents on proliferation rates in normal mammary glands and mammary cancers with their Chemopreventive efficacy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-11-01.

  • smoke induced microrna and related proteome alterations modulation by Chemopreventive Agents
    International Journal of Cancer, 2012
    Co-Authors: Silvio De Flora, R. M. Balansky, Vernon E Steele, Francesco Dagostini, Cristina Cartiglia, Mariagrazia Longobardi, Alberto Izzotti
    Abstract:

    Dysregulation of microRNAs (miRNAs) has important consequences on gene and protein expression since a single miRNA targets a number of genes simultaneously. This article provides a review of published data and ongoing studies regarding the effects of cigarette smoke (CS), either mainstream (MCS) or environmental (ECS), on the expression of miRNAs and related proteins. The results generated in mice, rats, and humans provided evidence that exposure to CS results in an intense dysregulation of miRNA expression in the respiratory tract, which is mainly oriented in the sense of downregulation. In parallel, there was an upregulation of proteins targeted by the downregulated miRNAs. These trends reflect an attempt to defend the respiratory tract by means of antioxidant mechanisms, detoxification of carcinogens, DNA repair, anti-inflammatory pathways, apoptosis, etc. However, a long-lasting exposure to CS causes irreversible miRNA alterations that activate carcinogenic mechanisms, such as modulation of oncogenes and oncosuppressor genes, cell proliferation, recruitment of undifferentiated stem cells, inflammation, inhibition of intercellular communications, angiogenesis, invasion, and metastasis. The miRNA alterations induced by CS in the lung of mice and rats are similar to those observed in the human respiratory tract. Since a number of miRNAs that are modulated by CS and/or Chemopreventive Agents are subjected to single nucleotide polymorphisms in humans, they can be evaluated according to toxicogenomic/pharmacogenomics approaches. A variety of cancer Chemopreventive Agents tested in our laboratory modulated both baseline and CS-related miRNA and proteome alterations, thus contributing to evaluate both safety and efficacy of dietary and pharmacological Agents.

Ahng Tony Kong - One of the best experts on this subject based on the ideXlab platform.

  • dietary cancer Chemopreventive Agents targeting inflammation and nrf2 signaling pathway
    Planta Medica, 2008
    Co-Authors: Tin Oo Khor, Ahng Tony Kong
    Abstract:

    Accumulating epidemiological and clinical evidence shows that chronic inflammation plays a critical role in neoplastic transformation and progression. Long-term users of selective cycloxygenase-2 (Cox-2) inhibitors (coxibs) and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have a reduced risk of developing colorectal cancer. However, the adverse gastrointestinal and cardiovascular side effects associated with these drugs have limited their routine use for cancer chemoprevention. Basic leucine zipper (bZIP) protein Nrf2, a key transcription factor mediating the antioxidant response is an important modulator of tumor susceptibility in mouse models. Mice lacking Nrf2 are more susceptible to carcinogenesis induced by carcinogens. Moreover, induction of the Nrf2 signaling pathway is essential for many food phytochemicals to exert their cancer Chemopreventive activity as demonstrated in many preclinical studies. It has been recently shown that the combination of coxibs or NSAIDs and natural phytochemicals can synergistically inhibit carcinogenesis in rodent models. This review will focus on the role of chronic inflammation and the Nrf2 signaling pathway in carcinogenesis and the feasibility of targeting these signaling pathways with dietary cancer Chemopreventive Agents and for cancer chemoprevention.

  • regulation of nrf2 nf κb and ap 1 signaling pathways by Chemopreventive Agents
    Antioxidants & Redox Signaling, 2005
    Co-Authors: Guoxiang Shen, Woosik Jeong, Ahng Tony Kong
    Abstract:

    The inhibition of carcinogenesis by Chemopreventive Agents has been demonstrated in many tumorigenesis animal models. The Chemopreventive mechanisms of those phytochemicals have been investigated extensively, though mostly in in vitro cell culture systems. The cellular signaling cascades mediated by transcription factors, including nuclear factor E2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), and activator protein-1 (AP-1), have been shown to play pivotal roles in tumor initiation, promotion, and progression processes. Thus, as demonstrated by previous substantive mechanistic studies, they appear to be ideal targets for cancer chemoprevention. In this review, we discuss the current progress and future challenges on our understanding of the molecular mechanisms in cancer chemoprevention by phytochemicals, focusing on the regulation of Nrf2, NF-κB, and AP-1 signaling pathways. Antioxid. Redox Signal. 7, 1648–1663.

  • modulatory properties of various natural Chemopreventive Agents on the activation of nf κb signaling pathway
    Pharmaceutical Research, 2004
    Co-Authors: Woosik Jeong, Inwha Kim, Ahng Tony Kong
    Abstract:

    Purpose. To study and compare effects of selected natural Chemopreventive Agents on the transcription activation of nuclear factor-kappa B (NF-κB) in human HT-29 colon cancer cells.

Mark Hannink - One of the best experts on this subject based on the ideXlab platform.

  • distinct cysteine residues in keap1 are required for keap1 dependent ubiquitination of nrf2 and for stabilization of nrf2 by Chemopreventive Agents and oxidative stress
    Molecular and Cellular Biology, 2003
    Co-Authors: Donna D Zhang, Mark Hannink
    Abstract:

    A common feature of diverse Chemopreventive Agents is the ability to activate expression of a genetic program that protects cells from reactive chemical species that, if left unchecked, would cause mutagenic DNA damage. The bZIP transcription factor Nrf2 has emerged as a key regulator of this cancer-preventive genetic program. Nrf2 is normally sequestered in the cytoplasm by a protein known as Keap1. Chemopreventive Agents allow Nrf2 to escape from Keap1-mediated repression, although the molecular mechanism(s) responsible for activation of Nrf2 is not understood. In this report, we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions. We have identified two critical cysteine residues in Keap1, C273 and C288, that are required for Keap1-dependent ubiquitination of Nrf2. Both sulforaphane, a Chemopreventive isothiocyanate, and oxidative stress enable Nrf2 to escape Keap1-dependent degradation, leading to stabilization of Nrf2, increased nuclear localization of Nrf2, and activation of Nrf2-dependent cancer-protective genes. We have identified a third cysteine residue in Keap1, C151, that is uniquely required for inhibition of Keap1-dependent degradation of Nrf2 by sulforaphane and oxidative stress. This cysteine residue is also required for a novel posttranslational modification to Keap1 that is induced by oxidative stress. We propose that Keap1 is a component of a novel E3 ubiquitin ligase complex that is specifically targeted for inhibition by both Chemopreventive Agents and oxidative stress.

  • distinct cysteine residues in keap1 are required for keap1 dependent ubiquitination of nrf2 and for stabilization of nrf2 by Chemopreventive Agents and oxidative stress
    Molecular and Cellular Biology, 2003
    Co-Authors: Donna D Zhang, Mark Hannink
    Abstract:

    A common feature of diverse Chemopreventive Agents is the ability to activate expression of a genetic program that protects cells from reactive chemical species that, if left unchecked, would cause mutagenic DNA damage. The bZIP transcription factor Nrf2 has emerged as a key regulator of this cancer-preventive genetic program. Nrf2 is normally sequestered in the cytoplasm by a protein known as Keap1. Chemopreventive Agents allow Nrf2 to escape from Keap1-mediated repression, although the molecular mechanism(s) responsible for activation of Nrf2 is not understood. In this report, we demonstrate that Keap1 does not passively sequester Nrf2 in the cytoplasm but actively targets Nrf2 for ubiquitination and degradation by the proteosome under basal culture conditions. We have identified two critical cysteine residues in Keap1, C273 and C288, that are required for Keap1-dependent ubiquitination of Nrf2. Both sulforaphane, a Chemopreventive isothiocyanate, and oxidative stress enable Nrf2 to escape Keap1-dependent degradation, leading to stabilization of Nrf2, increased nuclear localization of Nrf2, and activation of Nrf2-dependent cancer-protective genes. We have identified a third cysteine residue in Keap1, C151, that is uniquely required for inhibition of Keap1-dependent degradation of Nrf2 by sulforaphane and oxidative stress. This cysteine residue is also required for a novel posttranslational modification to Keap1 that is induced by oxidative stress. We propose that Keap1 is a component of a novel E3 ubiquitin ligase complex that is specifically targeted for inhibition by both Chemopreventive Agents and oxidative stress.

Fazlul H Sarkar - One of the best experts on this subject based on the ideXlab platform.

  • progress in nanotechnology based approaches to enhance the potential of Chemopreventive Agents
    Cancers, 2011
    Co-Authors: Irfana Muqbil, Fazlul H Sarkar, Ashiq Masood, Ramzi M Mohammad, Asfar S Azmi
    Abstract:

    Cancer chemoprevention is defined as the use of natural Agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Over the last two decades, multiple natural dietary compounds with diverse chemical structures such flavonoids, tannins, curcumins and polyphenols have been proposed as Chemopreventive Agents. These Agents have proven excellent anticancer potential in the laboratory setting, however, the observed effects in vitro do not translate in clinic where they fail to live up to their expectations. Among the various reasons for this discrepancy include inefficient systemic delivery and robust bioavailability. To overcome this barrier, researchers have focused towards coupling these Agents with nano based encapsulation technology that in principle will enhance bioavailability and ultimately benefit clinical outcome. The last decade has witnessed rapid advancement in the development of nanoChemopreventive technology with emergence of many nano encapsulated formulations of different dietary anticancer Agents. This review summarizes the most up-to-date knowledge on the studies performed in nanochemoprevention, their proposed use in the clinic and future directions in which this field is heading. As the knowledge of the dynamics of nano encapsulation evolves, it is expected that researchers will bring forward newer and far more superior nanoChemopreventive Agents that may become standard drugs for different cancers.

  • Targeting multiple signal pathways by Chemopreventive Agents for cancer prevention and therapy
    Acta Pharmacologica Sinica, 2007
    Co-Authors: Fazlul H Sarkar
    Abstract:

    In recent years, growing interest has been focused on the field of cancer prevention. Cancer prevention by Chemopreventive Agents offers significant promise for reducing the incidence and mortality of cancer. Chemopreventive Agents may exert their effects either by blocking or metabolizing carcinogens or by inhibiting tumor cell growth. Another important benefit of Chemopreventive Agents is their non-toxic nature. Therefore, Chemopreventive Agents have recently been used for cancer treatment in combination with chemotherapeutics or radiotherapy, uncovering a novel strategy for cancer therapy. This strategy opens a new avenue from cancer prevention to cancer treatment. In vitro and in vivo studies have demonstrated that Chemopreventive Agents could enhance the antitumor activity of chemotherapeutics, improving the treatment outcome. Growing evidence has shown that Chemopreventive Agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways, including Akt, NF-κB, c-Myc, cyclooxygenase-2, apoptosis, and others, suggesting a multitargeted nature of Chemopreventive Agents. However, further in-depth mechanistic studies, in vivo animal experiments, and clinical trials are needed to investigate the effects of Chemopreventive Agents in combination treatment of cancer with conventional cancer therapies. More potent natural and synthetic Chemopreventive Agents are also needed to improve the efficacy of mechanism-based and targeted therapeutic strategies against cancer, which are likely to make a significant impact on saving lives. Here, we have briefly reviewed the role of Chemopreventive Agents in cancer prevention, but most importantly, we have reviewed how they could be useful for cancer therapy in combination with conventional therapies.

  • using Chemopreventive Agents to enhance the efficacy of cancer therapy
    Cancer Research, 2006
    Co-Authors: Fazlul H Sarkar
    Abstract:

    Emerging evidence suggests that cancer preventative Agents might be combined with chemotherapy or radiotherapy for the more effective treatment of cancer. Recent studies suggest that genistein and other dietary compounds that prevent cancer may enhance the efficacy of cancer therapeutics by modifying the activity of key cell proliferation and survival pathways, such as those controlled by Akt, nuclear factor-κB, and cyclooxygenase-2. In this article, we summarize the findings of recent investigations of Chemopreventive Agents in combination with cancer treatment regimens. (Cancer Res 2006; 66(7):3347-50)

  • cell signaling pathways altered by natural Chemopreventive Agents
    Mutation Research, 2004
    Co-Authors: Fazlul H Sarkar
    Abstract:

    Abstract Epidemiological studies have indicated a significant difference in the incidence of cancers among ethnic groups, who have different lifestyles and have been exposed to different environmental factors. It has been estimated that more than two-thirds of human cancers, which are contributed by mutations in multiple genes, could be prevented by modification of lifestyle including dietary modification. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers. The in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3′-diindolylmethane (DIM), curcumin, (−)-epigallocatechin-3-gallate (EGCG), apigenin, etc., have shown inhibitory effects on human and animal cancers, suggesting that they may serve as Chemopreventive Agents. Experimental studies have also revealed that these components regulate the molecules in the cell signal transduction pathways including NF-κB, Akt, MAPK, p53, AR, and ER pathways. By modulating cell signaling pathways, these components, among other mechanisms, activate cell death signals and induce apoptosis in precancerous or cancer cells, resulting in the inhibition of cancer development and/or progression. This article reviews current studies regarding the effects of natural Chemopreventive Agents on cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of Chemopreventive Agents in cancer cells.

Gary J Kelloff - One of the best experts on this subject based on the ideXlab platform.

  • modulation of apoptosis by cigarette smoke and cancer Chemopreventive Agents in the respiratory tract of rats
    Carcinogenesis, 2001
    Co-Authors: Francesco Dagostini, R. M. Balansky, Alberto Izzotti, Gary J Kelloff, Ronald A Lubet, Silvio De Flora
    Abstract:

    Preclinical studies may elucidate the meaning of biomarkers applicable to epidemiologic studies and to clinical trials for cancer prevention. No study has explored so far the effect of cigarette smoke on apoptosis in vivo. We evaluated modulation of apoptosis in cells of the respiratory tract of smoke-exposed Sprague-Dawley rats both by morphological analysis and TUNEL method. In a first study, exposure of rats to mainstream cigarette smoke for either 18 or 100 consecutive days produced a significant and time-dependent increase in the proportion of apoptotic cells in the bronchial and bronchiolar epithelium. Oral N:-acetylcysteine did not affect the background frequency of apoptosis but significantly and sharply decreased smoke-induced apoptosis. In a second study, exposure of rats to a mixture of sidestream and mainstream smoke for 28 consecutive days resulted in a >10-fold increase in the frequency of pulmonary alveolar macrophages undergoing apoptosis. Dietary administration of either 5,6-benzoflavone, 1,2-dithiole-3-thione or oltipraz did not affect the frequency of smoke-induced apoptosis, whereas phenethyl isothiocyanate produced a further significant enhancement. Again, N-acetylcysteine and its combination with oltipraz significantly decreased smoke-induced apoptosis. In both studies exposure to smoke resulted in a sharp increase of cells positive for proliferating cell nuclear antigen (PCNA), which was unaffected by the examined Chemopreventive Agents. These findings highlight the concept that modulation of apoptosis has diversified meanings. Different meanings (as explained in the following lines). First, the apoptotic process is triggered as a defense system against genotoxic Agents, such as the components of cigarette smoke. The further induction produced by phenethyl isothiocyanate, favoring removal of damaged cells, represents an example of a detoxification mechanism. Inhibition of smoke-induced apoptosis by N:-acetylcysteine should be interpreted as an epiphenomenon of antigenotoxic mechanisms, as shown in parallel studies evaluating modulation of DNA alterations in the respiratory tract of the same animals. Thus, it is important to discriminate between whether the opposite modulation of apoptosis is per se a protective mechanism or the beneficial outcome of other mechanisms inhibiting genotoxicity.

  • efficacy of potential Chemopreventive Agents on rat colon aberrant crypt formation and progression
    Carcinogenesis, 2000
    Co-Authors: Michael J Wargovich, Vernon E Steele, Arnaldo Jimenez, Kathy Mckee, Marco A De Velasco, Johnnie Woods, Roger E Price, Kenneth N Gray, Gary J Kelloff
    Abstract:

    We assessed the effects of 78 potential Chemopreventive Agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol Agents were given during the period of AOM administration, whereas in the post-initiation assay the Chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The Agents were derived from a priority listing based on reports of Chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.

  • progress in cancer chemoprevention development of diet derived Chemopreventive Agents
    Journal of Nutrition, 2000
    Co-Authors: Gary J Kelloff, James A Crowell, Vernon E Steele, Ronald A Lubet, Winfred A Malone, Charles W Boone, Levy Kopelovich, Ernest T Hawk, Ronald Lieberman, Julia A Lawrence
    Abstract:

    Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as Chemopreventive Agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived Agents are included among the >40 promising Agents and agent combinations that are being evaluated clinically as Chemopreventive Agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived Agents are extracts, containing multiple compounds or classes of compounds. For developing such Agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the Chemopreventive potential of the extract, and these compounds may find use as Chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention.

  • aberrant crypts as a biomarker for colon cancer evaluation of potential Chemopreventive Agents in the rat
    Cancer Epidemiology Biomarkers & Prevention, 1996
    Co-Authors: Michael J Wargovich, Vernon E Steele, Arnaldo Jimenez, Marco A De Velasco, Roger E Price, Kenneth N Gray, C D Chen, L C Stephens, Gary J Kelloff
    Abstract:

    We assessed the effects of 41 potential Chemopreventive Agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon as the measure of efficacy. ACF were induced by the carcinogen azoxymethane in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last azoxymethane injection, animals were evaluated for the number of aberrant crypts detected in methylene blue-stained whole mounts of rat colon. The 41 Agents were derived from a priority listing that was based on reports of Chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. The list of Agents included representative examples of phytochemicals, vitamins, minerals, inhibitors of proliferation, inducers of Phase 1 and Phase 2 metabolism systems, nonsteroidal anti-inflammatory Agents, and differentiation Agents. Eighteen Agents were positive in the assay, significantly reducing the incidence of ACF at least in one of two doses tested. As a chemical class, the nonsteroidal anti-inflammatory drugs, which included ibuprofen, ketoprofen, piroxicam, and indomethacin, were most active; other less potent Agents were arginine, butylated hydroxyanisole, curcumin, diallyl sulfide, difluoromethylornithine, 18 beta-glycyrrhetinic acid, indole-3-carbinol, oltipraz, purpurin, rutin, and the sodium salts of butyrate, selenite, and thiosulfate. Twenty-three Agents did not inhibit ACF; included among these were several Agents that promoted the development of ACF at one or both doses tested: benzyl isothiocyanate,calcium glucarate, catechin, dihydroepiandosterone, fluocinolone acetonide,folic acid, levamisole, 2-mercaptoethanesulfonic acid, nordihydroguiaretic acid, potassium glucarate, propyl gallate, beta-sitosterol, sodium cromolyn, sodium molybdate, and sulfasalazine. The aberrant crypt assay demonstrates reasonable specificity and sensitivity in predicting which Agents are likely to prevent colon cancer.

  • screening of potential Chemopreventive Agents using biochemical markers of carcinogenesis
    Cancer Research, 1994
    Co-Authors: Sheela Sharma, Gary J Kelloff, Jill D Stutzman, Vernon E Steele
    Abstract:

    Ninety potential Chemopreventive Agents were screened using 6 chemoprevention-associated biochemical end points. These compounds were tested using rodent (tracheal epithelial or liver) cells and human cells [neonatal foreskin fibroblasts, bronchial epithelial cells, or human leukemic cells (HL-60)]. The effects measured were: ( a ) inhibition of 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced tyrosine kinase activity in HL-60 cells; ( b ) inhibition of TPA-induced ornithine decarboxylase (ODC) activity in rat tracheal epithelial cells; ( c ) inhibition of poly(ADP-ribose)polymerase in propane sultone-treated primary human fibroblasts; ( d ) inhibition of benzo[ a ]pyrene(B[ a ]P)-DNA binding in human bronchial epithelial cells; ( e ) induction of reduced glutathione in Buffalo rat liver cells; and ( f ) inhibition of TPA-induced free radical formation in primary human fibroblasts or HL-60 cells. Fifty compounds were highly effective in inhibiting TPA-induced tyrosine kinase activity. This assay identified compounds from a wide variety of chemical classes as effective inhibitors, including all the vitamins, retinoic acid analogues, protein kinase C inhibitors, and chemicals belonging to the amino acid category. Fifty-two chemicals were classified as highly positive compounds when examined for their ability to inhibit TPA-induced ODC activity. These Agents showed a dose-dependent inhibition or inhibition at all doses. Retinoids, in general, exhibited strong inhibition of ODC activity. A category of compounds showing dose-dependent inhibition were the sulfur compounds, especially the thiols and thiones. Among the natural products, terpenes were strong inhibitors of ODC. Forty-seven compounds were classified as strong inhibitors of poly(ADP-ribose)polymerase. In the carcinogen-DNA binding inhibition assay, 21 compounds were identified as strong inhibitors, which include phenolic compounds as well as sulfur compounds. Vitamins and their analogues were also good inhibitors. Testing for induced glutathione yielded 19 compounds that were good inducers. Sulfur-containing compounds and most of the phenolic compounds were also inducers of glutathione. Twenty compounds were highly positive for inhibition of TPA-induced free radical formation. A significant number of phenolic and sulfur compounds were again strong oxygen radical scavengers. Some antiinflammatory Agents were also identified as free radical inhibitors. In general, retinoids were quite active in all the assays. Eight compounds were positive in all of the six assays; these were vitamin C (ascorbic acid), bismuththiol, esculetin, etoperidone, folic acid, hydrocortisone, indole-3-carbinol, and tocopherol succinate. Agents that were positive in these assays may inhibit the carcinogenesis process by similar mechanisms in humans and are identified as candidates for development as Chemopreventive Agents. Agents capable of inhibiting multiple mechanisms are regarded as highly promising Agents for cancer chemoprevention.