Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
21
2
2002
Foreword
2
10.1615/JEnvironPatholToxicolOncol.v21.i2.10
Young-Joon
Surh
Seoul National University, South Korea
Yung-Jue
Bang
Cancer Research Institute, College of Medicine, Seoul National University
This issue of the Journal contains papers presented by speakers invited to the 10th CRI Symposium held on May 18 and 19,2001 at the Cancer Research Institute of the Seoul National University College of Medicine, Seoul, Korea. The title of the symposium was "Cyclooxygenase-2, a Molecular Target for Cancer Prevention."
Prostaglandins and the Regulation of Tumor Growth
9
10.1615/JEnvironPatholToxicolOncol.v21.i2.20
David
Bishop-Bailey
Department of Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, Queen Mary's University, London, UK EC1M 6BQ
Sara
Calatayud
Department of Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, Queen Mary's University, London, UK EC1M 6BQ
Timothy D.
Warner
Department of Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, Queen Mary's University, London, UK EC1M 6BQ
Timothy
Hla
Center for Vascular Biology, UCONN Health Center; 263 Farmington Avenue, Farmington, CT 06030
Jane A.
Mitchell
Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London, UK SW3 6LY
Increased expression of inducible cyclooxygenase (COX-2) is associated with a wide variety of tumors. In addition, inhibitors of COX have shown a great deal of promise in vitro and in animal models as potential antitumor therapies. COX enzymes use the substrate arachidonic acid to produce prostaglandin (PG)H2, the precursor to all the prostanoids. Therefore, the release of individual prostanoids depends on the abundance and functional coupling to individual PG synthase isoenzymes. Colony stimulating factors (CSFs) are also potential antitumor agents via their ability to augment the immune response. When COX-2 is expressed, the CSF, granulocyte macrophage (GM)-CSF, and granulocyte (G)-CSF are exquisitely sensitive to endogenous PGs. In addition, the ability of COX-2 to suppress GM-CSF release is mediated via traditional IP/EP prostanoid receptors linked to cAMP-dependent pathways. Therefore, inhibition of COX-2 in tumors may have the important side effect of enhancing the immune response. Recently, novel signaling pathways for PG derivatives have been discovered; in particular the PGD2 dehydration product 15-deoxy-D12,14-(15d)-PGJ2 was identified as a ligand for the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor (PPAR)-g. PPARg is present at high levels in a number of tumors, and is also present in endothelial cells. 15d-PGJ2 as well as other nonprostanoid PPARg ligands are antitumor, and antiangiogenic, by dramatically inhibiting the growth of tumor cells and endothelial cells by either causing terminal differentiation, and/or by inducing apoptosis. We have recently found that, in addition to IP and EP ligands generated by COX-2, PPARg ligands similarly inhibit GM-CSF release. Effecting individual prostanoid pathways at the level of COX expression, profile of PG products produced or selective PG receptor activation may produce novel therapies, either dependent or independent of CSF release, to target cancers.
The Role of Nitric Oxide and Cyclooxygenase-2 in Attenuating Apoptosis
10
10.1615/JEnvironPatholToxicolOncol.v21.i2.30
Andreas
von Knethen
University of Kaiserslautern, Faculty of Biology, Department of Cell Biology, Kaiserslautern, Germany
Bernhard
Brune
University of Kaiserslautern, Faculty of Biology, Department of Cell Biology, Kaiserslautern, Germany
The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome с relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 mM) or lipopolysaccharide/interferon-g/NG-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kВ as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kВ activation comprised p50/p65-heterodimer formation, IkВ degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kВ-site derived from the murine COX-2 promoter. A NF-kВ decoy approach (oligonucleotides directed against NF-kВ) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kВ and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
Redox Status-Dependent Regulation of Cyclooxygenases Mediates the Capsaicin-Induced Apoptosis in Human Neuroblastoma Cells
8
10.1615/JEnvironPatholToxicolOncol.v21.i2.40
Yong Soo
Lee
Department of Physiology, College of Medicine, Kwan-dong University, Kangnung, Korea
Eun Jin
Kwon
College of Pharmacy, Yeungnam University, Kyongsan, Korea
Da Qing
Jin
College of Pharmacy, Yeungnam University, Kyongsan, Korea
Seung Hee
Park
College of Pharmacy, Yeungnam University, Kyongsan, Korea
Young Shin
Kang
Department of Physiology, College of Medicine, Kwan-dong University, Kangnung, Korea
Keun
Huh
College of Pharmacy, Yeungnam University, Kyongsan, Korea
Jung-Ae
Kim
College of Pharmacy, Yeungnam University, Dae-Dong 214-1, Kyongsan 712-749, Korea
Cyclooxygenases (COX) appear to be involved in the mechanism of apoptosis in various cancer cells. In this study we investigated the role of COX in the capsaicin (Cap)-induced apoptosis in SK-N-SH human neuroblastoma cells. Cap induced decreased cell viability and apoptosis in a dose-dependent manner. Cap also significantly reduced the basal generation of reactive oxygen species (ROS) and lipid peroxidation in a time-dependent fashion. Cap markedly suppressed the expression of COX-1 and COX-2. Pretreatment with NS-398, a selective COX-2 inhibitor, or indomethacin, a nonselective COX inhibitor, significantly enhanced the Cap-induced decreased cell viability and apoptosis. Exogenous application of an oxidant, Н2О2, significantly prevented the Cap-induced apoptosis and suppressed the expression of COX isoforms. These results suggest that redox status-dependent regulation of COX expression may mediate apoptosis induced by Cap in human neuroblastoma cells.
Oxidant-Sensitive Transcription Factor and Cyclooxygenase-2 by Helicobacter pylori Stimulation in Human Gastric Cancer Cells
9
10.1615/JEnvironPatholToxicolOncol.v21.i2.50
Hyeyoung
Kim
Department of Pharmacology and Institute ofGastroen-terology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea
Joo Weon
Lim
Department of Pharmacology and Institute ofGastroen-terology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea
Jeong Yeon
Seo
Department of Pharmacology and Institute ofGastroen-terology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea
Kyung Hwan
Kim
Department of Pharmacology and Institute ofGastroen-terology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea
Helicobacter pylori (H. pylori) infection might activate nuclear factor-kB (NF-kB), an oxidant-sensitive transcription regulator of inducible expression of inflammatory genes such as cyclooxygenase-2 (COX-2). We studied the role of NF-kB on expression of COX-2 in H. pylori-stimulated gastric cancer cell lines by using antioxidants, glutathione (GSH), and N-acetylcysteine (NAC) as well as an NF-kB inhibitor, pyrrolidine dithiocarbamate (PDTC). Gastric adenocarcinoma cell lines derived from Caucasian (AGS) cells and Korean (SNU-484) cells were used to study the role of NF-kB on COX-2 expression by H. pylori. They were treated with GSH, NAC, or PDTC in the presence of H. pylori. mRNA expression and protein level for COX-2 were determined by Northern blot and RT-PCR analysis as well as Western blot analysis. NF-kB activation was examined by electrophoretic mobility shift assay. As a result, H. pylori induced a time-dependent expression of mRNA and protein for COX-2 via activation of NF-kB, which was inhibited by GSH, NAC, and PDTC in the cells. In conclusion, oxidant-sensitive transcription factor NF-kB may play a novel role in expression of COX-2 by H. pylori stimulation in gastric cancer cells.
Effects of Yakuchinone A and Yakuchinone В on the Phorbol Ester-Induced Expression of COX-2 and iNOS and Activation of NF-kB in Mouse Skin
9
10.1615/JEnvironPatholToxicolOncol.v21.i2.60
Kyung-Soo
Chun
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
Jee-Young
Kang
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
Ok Hee
Kim
Korea Food and Drug Administration, Seoul, South Korea
Hoil
Kang
Korea Food and Drug Administration, Seoul, South Korea
Young-Joon
Surh
Seoul National University, South Korea
Certain medicinal plants contain anti-inflammatory and antioxidative substances that can exert chemopreventive effects. Our previous studies have demonstrated that the methanol extract of Alpinia oxyphylla Miquel (Zingiberaceae) inhibits tumor promotion in mouse skin. Two major diarylheptanoids named yakuchinone A (l-[4'-hydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) and yakuchinone В (l-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-l-en-3-one) have been isolated from this medicinal plant. Both compounds have strong inhibitory effects on the synthesis of prostaglandins and leukotrienes in vitro. In the present work, we show that both yakuchinone A and yakuchinone В inhibit the expression of cyclooxygenase-2 (COX-2) and of inducible nitric oxide synthase (iNOS) as well as the expression of tumor necrosis factor (TNF)-a mRNA in mouse skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application on mouse skin of these diarylheptanoids also attenuated the TPA-induced DNA binding activity of the ubiquitous eukaryotic transcription factor NF-kB that plays a crucial role in regulating the expression of the aforementioned proinflammatory enzymes and cytokines in response to a wide variety of external stimuli. These findings suggest that diarylheptanoids contained in Alpinia oxyphylla down-regulate COX-2 and iNOS expression through suppression of NF-kB activation in the TPA-treated mouse skin.
Suppressive Effect of Natural Sesquiterpenoids on Inducible Cyclooxygenase (COX-2) and Nitric Oxide Synthase (iNOS) Activity in Mouse Macrophage Cells
8
10.1615/JEnvironPatholToxicolOncol.v21.i2.70
Sang Kook
Lee
College of Pharmacy, EwhaWomans University, Seoul, Korea
Chai-Hee
Hong
College of Pharmacy, EwhaWomans University, Seoul, Korea
Sun-Kyung
Huh
College of Pharmacy, Ewha Womans University, Seoul, Korea
Sun-Sook
Kim
College of Pharmacy, Ewha Womans University, Seoul, Korea
O-Jin
Oh
College of Pharmacy, Ewha Womans University, Seoul, Korea
Hye-Young
Min
College of Pharmacy, Ewha Womans University, Seoul, Korea
Kwang-Kyun
Park
College of Dental Medicine, Yonsei University, Seoul, Korea
Won-Yoon
Chung
College of Dental Medicine, Yonsei University, Seoul, Korea
Jae-Kwan
Hwang
Bioproducts Research Center, Yonsei University, Seoul, Korea
Prostaglandins and nitric oxide produced by inducible cyclooygenase (COX-2) and nitric oxide synthase (iNOS), respectively, have been implicated as important mediators in the processes of inflammation and carcinogenesis. These potential COX-2 and iNOS inhibitors have been considered as antiinflammatory and cancer chemopreventive agents. In this study, we investigated the effect of natural Sesquiterpenoids isolated from plants of the Zingiberaceae family on the activities of COX-2 and iNOS in cultured lipopolysaccharide (LPS)-activated mouse macrophage cell RAW 264.7 to discover new lead compounds as COX-2 or iNOS inhibitors. Xanthorrhizol, a sesquiterpenoid, isolated from the rhizome of Curcuma xanthorrhiza Roxb. (Zingiberaceae), exhibited a potent inhibition of COX-2 (IC50 = 0.2 g/mL) and iNOS activity (IC50 = 1.0 g/mL) in the assay system of prostaglandin E2 (PGE2) accumulation and nitric oxide production, respectively. Western blot analyses revealed that the inhibitory potential of xanthorrhizol on the COX-2 activity coincided well with the suppression of COX-2 protein expression in LPS-induced macrophages. In addition, Sesquiterpenoids b-turmerone and ar-turmerone isolated from the rhizome of Curcuma zedoaria Roscoe (Zingiberaceae) also showed a potent inhibitory activity of COX-2 (b-turmerone, IC50 = 1.6 mg/mL; ar-turmerone, IC50 = 5.2 mg/mL) and iNOS (b-turmerone, IC50 = 4.6 mg/mL; ar-turmerone, IC50 = 3.2 mg/mL). These results suggest that natural sesquiterpenoids from C. xanthorrhiza and C. zedoariu might be lead candidates for further developing COX-2 or iNOS inhibitors possessing cancer chemopreventive or anti-inflammatory properties.
COX-2 and Prostanoid Receptors: Good Targets for Chemoprevention
5
10.1615/JEnvironPatholToxicolOncol.v21.i2.80
Toshihiko
Kawamori
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104-0045 Japan
Keiji
Wakabayashi
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104-0045 Japan
Accumulating evidence indicates that COX-2 inhibitors are involved in colon and breast cancer development. Our previous studies indicated that nimesulide and celecoxib, selective COX-2 inhibitors, show inhibitory effects of intestinal" carcinogenesis in azoxymethane-treated rats and mice and in Min mice models. We recently found that nimesulide suppressed PhIP-induced breast cancer in female SD rats in which COX-2 protein was overexpressed. These results led us to investigate the effects of prostaglandin E2(PGE2) in the target tissues. PGE2 showed its biological activity through binding to its membrane receptors, EP1~4. We also investigated the effects of EP receptors on colon carcinogenesis. We used receptor knockout mice and selective receptor antagonists. Our results indicated that the EP1 receptor plays a pivotal role in colon carcinogenesis. Selective EP1 receptor antagonists may be a new class of chemopreventive agents against colon cancer.
Novel Approaches for Colon Cancer Prevention by Cyclooxygenase-2 Inhibitors
10
10.1615/JEnvironPatholToxicolOncol.v21.i2.90
Bandaru S.
Reddy
Nutritional Carcinogenesis and Chemoprevention Program, American Health Foundation, Valhalla, NY 10595
Chinthalapally V.
Rao
Nutritional Carcinogenesis and Chemoprevention Program, American Health Foundation, Valhalla, NY 10595
During recent years, multidisciplinary studies in epidemiology and molecular biology, as well as preclinical studies, have contributed much to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. Clinical trials with NSAIDs have demonstrated that NSAID treatment caused regression of preexisting colon adenomas in patients with familial adenomatous polyposis. Preclinical efficacy studies have provided compelling evidence that several phytochemicals with antiinflammatory properties and NSAIDs act to retard, block, or reverse colon carcinogenesis. Equally exciting are opportunities for effective chemoprevention with selective cyclooxygenase-2 (COX-2) inhibitors including celecoxib and rofecoxib in a variety of preclinical models of colon cancer. Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity. Multistep process of carcinogenesis has provided substantial insights into the mechanisms by which naturally occurring and synthetic antiinflammatory agents modulate these events leading to suppression of tumorigenesis. Growing knowledge in this area has brought about innovative approaches using a combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance would be to identify molecular targets that are critical in the growth and survival of the malignant colorectal cell and are modulated by NSAIDs and COX-2 inhibitors.
In Vitro Evidence of the Role of COX-2 in Attenuating Gastric Inflammation and Promoting Gastric Carcinogenesis
12
10.1615/JEnvironPatholToxicolOncol.v21.i2.100
Ki-Baik
Hahm
Departments of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
Ho-Yeong
Lim
Departments of Oncology, Ajou University School of Medicine, Suwon, Korea
Seonghyang
Sohn
Departments of Dermatology, Ajou University School of Medicine, Suwon, Korea
Hyuk-Jae
Kwon
Departments of Dermatology, Ajou University School of Medicine, Suwon, Korea
Ki-Myung
Lee
Departments of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
Jeong-Sang
Lee
College of Pharmacology, Seoul National University, Seoul, Korea
Young-Joon
Surh
Seoul National University, South Korea
Young-Bae
Kim
Departments of Pathology,5 Ajou University School of Medicine, Suwon, Korea
Hee-Jae
Joo
Departments of Pathology,5 Ajou University School of Medicine, Suwon, Korea
Won-Seok
Kim
School of Engineering The Robert Gordon University Schoolhill, Aberdeen, AB10 1FR, UK
Seung-Won
Cho
Departments of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
Although gastric adenocarcinoma is one of the most common malignancies in the world, little is known about its exact molecular processes in development and progression. Recent studies suggest that COX-2 is important in carcinogenesis of gastrointestinal cancers, and is especially involved in carcinogenesis in a mouse model of familial adenomatosis polyposis. To understand the role of COX-2 in gastric carcinogenesis and Helicobacter pylori-associated gastritis, we measured COX-2 expression in 170 human gastric carcinoma tissues by immunohistochemical analysis and compared the expression of COX-2 in paired tissues obtained from normal-looking and cancer-bearing mucosa. Further evidence of the involvement of COX-2 in gastritis and gastric carcinogenesis was obtained by establishing stable cell lines overexpressing COX-2. After subcloning of COX-2 into pCB7 mammalian expression vector, two stable cell lines named MKN-28-COX-2 and MKN-45-COX-2 were generated by transfection of COX-2 cDNA. To understand the effect of COX-2 on gastritis, we performed an electrophoretic mobility shift assay of NF-kB (inflammation-associated transcription factor), and measured malondialdehyde levels and chemiluminescence activities in both mock-transfected MKN and MKN-COX-2 cells after stimulation of H. pylori (1 x 106 CFU/mL) and neutrophils (102 cells/mL). A marked attenuation ofNF-kB bindings and generation of free radicals was observed in COX-2 overexpressed cells. Another set of experiments, including the growth inhibition by TGF-b treatment, Matrigel invasion assay, and apoptosis assay, was done. COX-2 showed the advantage of the escape from the growth inhibition by TGF-b through decreasing TGF-b RII expression and increased cell invasiveness. In conclusion, COX-2 expression seems to be induced to attenuate the degree of atrophic gastritis, the initial event in gastric carcinogenesis, and promote gastric carcinogenesis.
Increased Expression of COX-2 in the Development of Human Lung Cancers
5
10.1615/JEnvironPatholToxicolOncol.v21.i2.110
Takashi
Takahashi
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Ken-ichi
Kozaki
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Yasushi
Yatabe
Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya, Japan
Hiroyuki
Achiwa
Department of Internal Medicine, Aichi Cancer Center Hospital, Nagoya, Japan
Toyoaki
Hida
Department of Internal Medicine, Aichi Cancer Center Hospital, Nagoya, Japan
It is well accepted that an increase in the expression of cyclooxygenase-2 (COX-2), a key inducible enzyme involved in the production of prostaglandins and other eicosanoids, may play a significant role in carcinogenesis in addition to its well-known role in inflammatory reactions. Whereas previous studies were largely confined to colorectal tumorigenesis, we have shown that a significantly increased expression of COX-2 may also play a role in the development of lung cancer. COX-2 expression was found to be frequently elevated in lung cancer, especially in adenocarcinoma, and the proportion of lung cancer cells with marked COX-2 expression was much higher in lymph node metastases than in the corresponding primary tumors. It was also shown that early stage adenocarcinoma patients with increased COX-2 expression who were surgically treated had a shorter survival. Our studies, which used high- and low-metastatic human lung cancer cell sublines established in our laboratory, revealed an association between metastatic capabilities and COX-2 expression levels: COX-2-specific inhibitors could inhibit in vitro the invasion of the highly metastatic NCI-H460-LNM35 clone through Matrigel-containing basement membrane components as well as the spontaneous in vivo metastasis in SCID mice. Taken together, these findings suggest that an increase in COX-2 expression may be associated with the development of lung cancer and possibly with the acquisition of an invasive and metastatic phenotype.
Is Cyclooxygenase-2 Important in Skin Carcinogenesis?
9
10.1615/JEnvironPatholToxicolOncol.v21.i2.120
Susan M.
Fischer
The University of Texas M.D. Anderson, Department of Carcinogenesis, Science Park-Research Division, Smithville, TX 78957
Our studies have focused on the role of arachidonic acid and its products in chemically and UV light-induced murine models of skin carcinogenesis, with an emphasis on determining the importance of prostaglandins (PGs), which are synthesized by the two isoforms ofcyclooxygenase (COX). Different types of tumor promoters elevate COX-2 expression in keratinocytes, with little change in COX-1, suggesting that there are multiple signaling pathways by which COX-2 expression can be regulated. We found that the expression of both COX isoforms is increased by treatment with PGs and that this autoregulation occurs via PG receptors linked to a cAMP signaling pathway. We also observed that COX-2 is constitutively upregulated in papillomas and carcinomas from either chemical initiation-promotion or UV-irradiation carcinogenesis experiments. We next investigated cis- and transacting factors required for COX-2 expression. Two regions of the COX-2 promoter, an E box and a nuclear factor-IL6 (NF-IL6) site, were identified as positive regulatory elements through transient transfection with luciferase reporter vectors containing various 5’-flanking regions of the promoter. We found that overexpression of COX-2 in tumors maybe caused by a dysregulation in the expression pattern of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. To demonstrate the importance of PG synthesis in the carcinogenesis process, several nonsteroidal anti-inflammatory (NSAIDs) drugs were administered either orally or topically during UV carcinogenesis. Dietary administration of indomethacin, piroxicam, or the selective COX-2 inhibitor celecoxib prevented the development of UV-induced skin cancers by up to 85%. In addition, celecoxib had therapeutic efficacy in that it caused regression of preexisting tumors. Topical administration ofindomethacin after each UV exposure was also effective, suggesting that a postexposure approach to skin cancer prevention maybe effective. Collectively, these studies suggest that prostaglandins play a critical role in skin cancer development.
Epidemiological and Clinical Aspects of Nonsteroidal Anti-inflammatory Drugs and Cancer Risks
9
10.1615/JEnvironPatholToxicolOncol.v21.i2.130
Edgar M.
Moran
Cancer Program, Long Beach VA Medical Center, Long Beach, CA, USA; Department of Veterans Administration Medical Center, University of California Irvine, Irvine, CA, USA
It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases may be avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2.
BOOK REVIEW: Textbook of Palliative Nursing by Betty Rolling Ferrer & Nessa Coyle
1
10.1615/JEnvironPatholToxicolOncol.v21.i2.140
Pegi
Black
Geriatrics Extended Care Organization, VA Long Beach Healthcare System, Long Beach, CA
Edgar M.
Moran
Cancer Program, Long Beach VA Medical Center, Long Beach, CA, USA; Department of Veterans Administration Medical Center, University of California Irvine, Irvine, CA, USA