RESUMEN
Increased prostaglandins (PGs) are associated with many inflammatory pathophysiological conditions; and are synthesized from arachidonic acid by either of 2 enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2). Recent epidemiologic, expression, and pharmacologic studies suggest COX-2 derived metabolites also play a functional role in the maintenance of tumor viability, growth and metastasis. Archival and/or prospectively collected human tissues were prepared for immunohistochemistry, and representative cases assayed via Western blot, RT-PCR, or TAQman analysis. Consistent overexpression of COX-2 was observed in a broad range of premalignant, malignant, and metastatic human epithelial cancers. COX-2 was detected in ca. 85% of the hyperproliferating, dysplastic, and neoplastic epithelial cells, and in the existing and angiogenic vasculature within and adjacent to hyperplastic/neoplastic lesions. These data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers.
Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/metabolismo , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/enzimología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Proteínas de la Membrana , Neoplasias Glandulares y Epiteliales/prevención & control , Prostaglandina-Endoperóxido Sintasas/genéticaRESUMEN
Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflammatory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mechanisms, which include simple competitive, as well as slow binding and irreversible inhibition. In general, most NSAIDs inhibit COX-1 and -2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme. Several of these inhibitors, with varying selectivity, have been utilized to probe the mechanisms of COX inhibition. Results from analysis of both steady-state and time-dependent inhibition were compared. A generalized mechanism for inhibition, consisting of three sequential reversible steps, can account for the various types of kinetic behaviour observed with these inhibitors.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Animales , Unión Competitiva , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Isoxazoles/farmacología , Cinética , Meloxicam , Ratones , Prostaglandina-Endoperóxido Sintasas , Pirazoles/farmacología , Ovinos , Sulfonamidas/farmacología , Tiazinas/farmacología , Tiazoles/farmacologíaRESUMEN
Recent chemopreventive studies in our laboratories showed that the COX-2 inhibitor, celecoxib, inhibited the induction of mammary cancer by 7,12-dimethylbenz(a)anthracene (DMBA). In this study, we examined the relative chemopreventive effect of varying doses of celecoxib on the development and growth of DMBA-induced rat mammary tumors. At 10 days prior to receiving a single intragastric dose of 15 mg DMBA/rat, female Sprague-Dawley rats were fed a control chow diet or diets containing 250, 500, 1000 or 1500 ppm celecoxib until termination of the experiment. Administration of increasing doses of celecoxib inhibited mammary tumor incidence and multiplicity as well as tumor volume in a dose-dependent manner. At 122 days post DMBA-intubation, mammary tumor incidence was 100% in the control rats compared to 80%, 50%, 45% and 25% in rats receiving 250, 500, 1000 or 1500 ppm celecoxib, respectively (p<0.001). Similarly, tumor multiplicity and tumor volume were significantly reduced by increasing the dose of celecoxib from 250 to 1500 ppm in the diet. The control rats had an average of 3.46 tumors/rat compared to 1.80, 1.00, 0.75 and 0.50 tumors/rat in animals receiving 250, 500, 1000 or 1500 ppm celecoxib, respectively (p<0.001). Average tumor volumes in rats fed 250, 500, 1000 or 1500 ppm celecoxib were 0.42, 0.34, 0.31 and 0.16 cm3 compared to 1.29 cm3 in the control rats (p<0.001). There was a concomitant increase in the steady-state serum concentration of celecoxib with the dose. These results indicate that, in this rat model, the chemopreventive effect of celecoxib against breast cancer is dose-dependent and that celecoxib is effective even at lower dose levels.
Asunto(s)
Anticarcinógenos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Neoplasias Mamarias Experimentales/prevención & control , Sulfonamidas/farmacología , 9,10-Dimetil-1,2-benzantraceno/antagonistas & inhibidores , Animales , Carcinógenos/antagonistas & inhibidores , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Relación Dosis-Respuesta a Droga , Femenino , Isoenzimas/antagonistas & inhibidores , Isoenzimas/biosíntesis , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Pirazoles , Ratas , Ratas Sprague-DawleyRESUMEN
Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in the prevention of human cancers. A number of preclinical studies have also suggested that inhibition of cyclooxygenase (COX) with NSAIDs has an anticancer effect in animal models of colon, urinary bladder, skin, and breast. In these studies, we evaluated the COX-2 inhibitor celecoxib in two rodent models of urinary bladder cancer. Male B6D2F1 mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) developed transitional and squamous cell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mice. Groups of mice received various daily doses of celecoxib in the diet (1250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 12 weekly doses of OH-BBN. Mice were checked weekly for the presence of palpable urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpable bladder lesions, which necessitated sacrifice of the mice, was 40% in the OH-BBN control group. In contrast, only 10% of all celecoxib-treated mice required sacrifice before the scheduled termination of the experiment, implying that all three doses of celecoxib inhibited the formation of large palpable lesions. Celecoxib did not significantly alter the incidence of preneoplastic bladder lesions, but did dose-dependently decrease the total number of urinary bladder cancers/mouse, palpable plus microscopic, by 77, 57, and 43% at dosages of 1250, 500, and 200 mg of celecoxib/kg of diet, respectively. In the second model, female Fischer-344 rats were administered OH-BBN twice/week for a period of 8 weeks. After 8 months, all rats developed preneoplastic lesions, whereas roughly 60% of the rats developed relatively small urinary bladder cancers. Rats were treated continually with celecoxib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior to the initial OH-BBN treatment or beginning 1 week following the last OH-BBN treatment. Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prior to OH-BBN administration decreased cancer incidence roughly 65%, celecoxib treatment initiated beginning 1 week after the last dose of OH-BBN profoundly decreased cancer incidence (>95%). Celecoxib did not alter the body weights of the mice or rats, or cause other signs of toxicity at any of the doses studied. Taken together these results demonstrate that: (a) celecoxib effectively inhibits tumor growth and enhances survival in the mouse model of urinary bladder cancer; and (b) celecoxib profoundly inhibits development of urinary bladder cancers in the rat model even when administered following the last dose of OH-BBN. Clinical trials will be necessary to determine whether COX-2 inhibitors will provide a clinical benefit in human bladder cancer.
Asunto(s)
Anticarcinógenos/farmacología , Butilhidroxibutilnitrosamina/toxicidad , Carcinógenos/antagonistas & inhibidores , Inhibidores de la Ciclooxigenasa/farmacología , Sulfonamidas/farmacología , Neoplasias de la Vejiga Urinaria/prevención & control , Animales , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/prevención & control , Carcinoma de Células Transicionales/inducido químicamente , Carcinoma de Células Transicionales/enzimología , Carcinoma de Células Transicionales/prevención & control , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Isoenzimas/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Especificidad de Órganos , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/prevención & control , Prostaglandina-Endoperóxido Sintasas , Pirazoles , Ratas , Ratas Endogámicas F344 , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/enzimologíaRESUMEN
Epidemiological and experimental studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the relative risk of human cancer, including breast cancer. Recently, research studies in our laboratories have shown that the selective cyclooxygenase-2 (COX-2) blocker, Celecoxib, given daily in the diet, significantly inhibited the induction of rat mammary tumors by 7, 12-dimethylbenz(a)anthracene (DMBA). These studies were extended to evaluate Celecoxib for its effectiveness as an antineoplastic agent in this rat mammary tumor model. We examined the growth inhibitory effects of Celecoxib, given daily in the diet, on the volume and the number of established mammary tumors, vis-a-vis the cancer load (CL). Tumors continued to grow actively in control rats fed chow diet only. In contrast, the Celecoxib-supplemented diet (1500 mg/kg diet) significantly decreased the size of the mammary tumors in rats over the 6 week treatment period, resulting in an average reduction in tumor volume of approximately 32%, relative to the baseline volume (p<0.04). At the end of the 6 week treatment period, average tumor volume was 1.45 cm3 and 0.13 cm3 in the control and Celecoxib treated rats respectively. Tumor regression occurred in 90% of the rats. In addition, new tumors continued to emerge in the control group, in contrast to their significantly decreasing numbers in the Celecoxib treated group over the same time period (p<0.05). These results indicate that Celecoxib has significant antineoplastic activity, in addition to its anticarcinogenic effects.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Sulfonamidas/farmacología , 9,10-Dimetil-1,2-benzantraceno , Adenocarcinoma/inducido químicamente , Adenocarcinoma/patología , Animales , Peso Corporal/efectos de los fármacos , Carcinógenos , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Ingestión de Alimentos/efectos de los fármacos , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Prostaglandina-Endoperóxido Sintasas , Pirazoles , Ratas , Ratas Sprague-DawleyRESUMEN
Epidemiological and animal studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia. We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam. Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam. To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.
Asunto(s)
Poliposis Adenomatosa del Colon/prevención & control , Anticarcinógenos/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Poliposis Adenomatosa del Colon/metabolismo , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Antineoplásicos/farmacología , Celecoxib , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Modelos Animales de Enfermedad , Femenino , Isoenzimas/metabolismo , Masculino , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles , Especificidad por Sustrato , Sulfonamidas/farmacología , Tromboxano B2/metabolismoRESUMEN
A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Inhibidores de la Ciclooxigenasa/síntesis química , Imidazoles/síntesis química , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Artritis Experimental/tratamiento farmacológico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/toxicidad , Perros , Edema/tratamiento farmacológico , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Hiperalgesia/tratamiento farmacológico , Imidazoles/química , Imidazoles/farmacología , Imidazoles/toxicidad , Intestinos/efectos de los fármacos , Intestinos/patología , Proteínas de la Membrana , Ratones , Nitrilos/síntesis química , Piridinas/química , Ratas , Estómago/efectos de los fármacos , Estómago/patología , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaAsunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/farmacología , Isoxazoles/farmacología , Prostaglandina-Endoperóxido Sintasas/farmacología , Acilación , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Perros , Inyecciones , Isoxazoles/administración & dosificación , Macaca fascicularis , Masculino , RatasRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the relative risk of breast cancer. This prompted our investigation of the chemopreventive potential of celecoxib, a specific cyclooxygenase 2 blocker, against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in female Sprague Dawley rats. Treatment with celecoxib was examined and compared to treatment with the general NSAID, ibuprofen, and to a control group receiving only dimethylbenz(a)anthracene. Dietary administration of celecoxib (1500 ppm) produced striking reductions in the incidence, multiplicity, and volume of breast tumors relative to the control group (68%, 86%, and 81%, respectively; P < 0.001). Ibuprofen also produced significant effects, but of lesser magnitude (40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the chemopreventive activity of NSAIDs against breast cancer and provide the first evidence that a cyclooxygenase 2 blocking agent, celecoxib, possesses strong chemopreventive activity against mammary carcinogenesis.
Asunto(s)
Anticarcinógenos/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/farmacología , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/prevención & control , Prostaglandina-Endoperóxido Sintasas/farmacología , Sulfonamidas/uso terapéutico , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Anticarcinógenos/efectos adversos , Anticarcinógenos/sangre , Anticarcinógenos/farmacología , Peso Corporal/efectos de los fármacos , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/sangre , Inhibidores de la Ciclooxigenasa/farmacología , Femenino , Ibuprofeno/efectos adversos , Ibuprofeno/sangre , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Isoenzimas/metabolismo , Neoplasias Mamarias Animales/inducido químicamente , Neoplasias Mamarias Animales/tratamiento farmacológico , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles , Ratas , Ratas Sprague-Dawley , Especificidad por Sustrato , Sulfonamidas/efectos adversos , Sulfonamidas/sangre , Sulfonamidas/farmacologíaRESUMEN
We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.
Asunto(s)
Anticarcinógenos/farmacología , Anticarcinógenos/uso terapéutico , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Isoenzimas/farmacología , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Prostaglandina-Endoperóxido Sintasas/farmacología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Animales , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Humanos , Inmunohistoquímica , Isoenzimas/biosíntesis , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Pirazoles , RatasAsunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Inhibidores Enzimáticos/síntesis química , Isoenzimas/farmacología , Isoxazoles/síntesis química , Prostaglandina-Endoperóxido Sintasas/farmacología , Sulfonamidas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Ciclooxigenasa 2 , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Humanos , Isoenzimas/sangre , Isoxazoles/farmacología , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/sangre , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Sulfonamidas/farmacologíaRESUMEN
Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as cyclooxygenases (COXs). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, ie., celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, ie., continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats. We also measured the steady-state levels of celecoxib in the plasma of animals given this inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib. At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/ progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, ie., 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence (P < 0.01 to P < 0.0001) as well as the multiplicity (P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon (P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume (P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps.
Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias del Colon/prevención & control , Inhibidores de la Ciclooxigenasa/uso terapéutico , Sulfonamidas/uso terapéutico , Administración Oral , Animales , Azoximetano/toxicidad , Celecoxib , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Progresión de la Enfermedad , Isoenzimas/metabolismo , Masculino , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles , Ratas , Ratas Endogámicas F344 , Sulfonamidas/administración & dosificación , Factores de TiempoRESUMEN
Epidemiological and dietary studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mechanism involving inhibition of cyclooxygenase (COX)-2, which is overexpressed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a specific COX-2 inhibitor) and indomethacin (a nonspecific NSAID), to block UV-induced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 or 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respectively) in tumor yield. Indomethacin (4ppm) reduced tumor yield by 78%. Although both acute and chronic UV exposure increased cell proliferation and edema, neither compound reduced these parameters. In contrast, UV-induced prostaglandin synthesis in the epidermis was effectively blocked by both compounds. UV-induced increases in COX-2 expression in skin were also not altered in any of the treatment groups. Similarly, tumors that constitutively express high levels of COX-2 displayed no reduction by treatment with celecoxib or indomethacin. The dramatic protective effects of celecoxib suggests that specific COX-2 inhibitors may offer a way to safely reduce the risk of skin cancer in humans.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Indometacina/farmacología , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Cutáneas/prevención & control , Sulfonamidas/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Peso Corporal/efectos de los fármacos , Celecoxib , División Celular , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Dinoprostona/biosíntesis , Relación Dosis-Respuesta en la Radiación , Conducta Alimentaria/efectos de los fármacos , Isoenzimas/efectos de los fármacos , Ratones , Ratones Pelados , Neoplasias Inducidas por Radiación/patología , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Pirazoles , Neoplasias Cutáneas/patología , Rayos UltravioletaAsunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Prostaglandinas/fisiología , Animales , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Celecoxib , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Humanos , Isoenzimas/metabolismo , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles , Sulfonamidas/farmacologíaRESUMEN
A series of methysulfonyl or sulfonamido substituted 4,5-diaryloxazole were prepared and evaluated for their ability to inhibit the inducible form of cyclooxygenase (COX-2) in vitro and in vivo. Several unique substitution patterns were identified that led to potent and selective inhibitors of COX-2. In general, 2-trifluoromethly-4,5-diaryloxazoles substituted with a methylsulfonyl or sulfonamido group were particularly potent inhibitors. One of the more potent compounds with a selectivity for COX-2 of about 800 fold was 4b (SC-299). SC-299, a highly fluorescent molecule, may be useful for spectroscopic studies on preferential inhibitor binding to COX-2.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/efectos de los fármacos , Oxazoles/farmacología , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Humanos , Proteínas de la MembranaRESUMEN
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.
Asunto(s)
Isoenzimas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Sulfonas/química , Tiazoles/síntesis química , Animales , Ciclooxigenasa 2 , Concentración 50 Inhibidora , RatasRESUMEN
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.
Asunto(s)
Isoenzimas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Sulfonamidas/química , Tiazoles/síntesis química , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/síntesis química , Humanos , Proteínas de la Membrana , Modelos Químicos , RatasRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki=10-16 microM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki=11-15 microM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact=0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50=4-19 microM) and the inactivation component on COX-2 (IC50=0.003-0.006 microM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity.
Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Inhibidores de la Ciclooxigenasa/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Sulfonamidas/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Celecoxib , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/metabolismo , Humanos , Ibuprofeno/farmacología , Indometacina/farmacología , Concentración 50 Inhibidora , Isoenzimas/metabolismo , Cinética , Masculino , Proteínas de la Membrana , Ratones , Naproxeno/farmacología , Oxígeno/metabolismo , Pirazoles , Ovinos , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Tetrametilfenilendiamina/metabolismo , TermodinámicaRESUMEN
The formation of new blood vessels by angiogenesis to provide adequate blood supply is a key requirement for the growth of many tumors. While normal blood vessels expressed the COX-1 enzyme, new angiogenic endothelial cells expressed the inducible COX-2. We evaluated the role of COX inhibitors in the mouse corneal micropocket assay in which angiogenesis is driven by the addition of a Hydron pellet containing basic fibroblast growth factor (bFGF). Neovascular areas were measured with a slit lamp five days after pellet implantation into the corneal stroma. All animals containing implants with bFGF (90 ng) developed intensive areas of neovascularization, whereas the controls implanted with the Hydron pellet alone did not. Indomethacin (a nonselective COX-1/COX-2 inhibitor) and SC-236 (a COX-2-selective inhibitor) inhibited angiogenesis in a dose-dependent manner. Importantly, the indomethacin-treated mice developed severe gastrointestinal toxicity at the efficacious dose of 3 mg/kg/day. By contrast, gastrointestinal lesions were not observed, and platelet COX-1 activity was unaffected, at anti-angiogenic doses of SC-236 (1-6 mg/kg/day). Furthermore, a COX-1-selective inhibitor, SC-560, was ineffective at doses up to 10 mg/kg, a dose that completely blocked platelet COX-1 activity in these mice. SC-236 was also effective in reducing angiogenesis driven by bFGF, vascular endothelium growth factor (VEGF), or carrageenan in the matrigel rat model. Finally, in several tumor models, SC-236 consistently and effectively inhibited tumor growth and angiogenesis. This novel antiangiogenic activity of COX-2 inhibitors indicates their potential therapeutic utility in several types of cancer.
Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/farmacología , Isoenzimas/fisiología , Neovascularización Patológica/tratamiento farmacológico , Prostaglandina-Endoperóxido Sintasas/farmacología , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Humanos , Proteínas de la Membrana , Ratones , Neoplasias/irrigación sanguínea , Neoplasias Experimentales/irrigación sanguínea , RatasRESUMEN
The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.