Chemoprevention of Aerodigestive Tract Cancers

Kim, Edward S.; Hong, Waun Ki; Khuri, Fadlo R.

doi:10.1146/annurev.med.53.082901.104015

Cited by 41 publications

(35 citation statements)

References 67 publications

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“…The 5-year survival of patients diagnosed with esophageal SCC is around 30% (4). Clearly, the development of cancer chemopreventive agents for oral cavity and esophageal cancer is an important research priority (3,(5)(6)(7), and for this, animal models are needed.…”

Section: Introductionmentioning

confidence: 99%

Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

Tang

Knudsen

Bemis

et al. 2004

Clinical Cancer Research

325

363

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Purpose: Squamous cell carcinoma of the oral cavity is one of the most common human neoplasms, and prevention of these carcinomas requires a better understanding of the carcinogenesis process and a model system in which cancer chemoprevention agents can be tested. We have developed a mouse model using the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in the drinking water to induce tumorigenesis in the mouse oral cavity.Experimental Design: 4-NQO was delivered by tongue painting or drinking water to two mouse strains, CBA and C57Bl/6. The incidences of oral cavity carcinogenesis were then compared. In addition, we examined the expression of some of the molecular markers associated with the process of human oral cavity and esophageal carcinogenesis, such as keratin (K) 1, K14, p16, and epidermal growth factor receptor, by immunohistochemistry.Results: After treatment with 4-NQO in the drinking water, massive tumors were observed on the tongues of both CBA and C57Bl/6 female mice. Pathological analyses indicated that flat squamous dysplasias, exophytic papillary squamous tumors (papillomas), and invasive squamous cell carcinomas were present. Immunohistochemistry analyses showed that 4-NQO changed the expression patterns of the intermediate filament proteins K14 and K1. K14 was expressed in the epithelial suprabasal layers, in addition to the basal layer, in tongues from carcinogen-treated animals. In contrast, control animals expressed K14 only in the basal layer. Moreover, we observed more bromodeoxyuridine staining in the tongue epithelia of 4-NQO-treated mice. Reduced expression of the cell cycle inhibitor, p16, was observed, whereas 4-NQO treatment caused an increase in epidermal growth factor receptor expression in the mouse tongues. Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQOtreated mice. However, no tumors were observed in the remainder of digestive tract (including the forestomach, intestine, and colon) or in the lungs or livers of 4-NQOtreated mice. These results indicate that this murine 4-NQOinduced oral and esophageal carcinogenesis model simulates many aspects of human oral cavity and esophageal carcinogenesis.Conclusions: The availability of this mouse model should permit analysis of oral cavity and esophageal cancer development in various mutant and transgenic mouse strains. This model will also allow testing of cancer chemopreventive drugs in various transgenic mouse strains.

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Section: Introductionmentioning

confidence: 99%

Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

Tang

Knudsen

Bemis

et al. 2004

Clinical Cancer Research

325

363

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“…One chemopreventive approach that has received attention is the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs). It is now generally accepted that NSAIDs prevent the development of colorectal cancer (Kim et al, 2002), and there is some evidence for a protective effect for other types of cancer (Khuder and Mutgi, 2001;Corley et al, 2003). Proposed mechanisms of these effects include induction of apoptosis, inhibition of angiogenesis, and direct inhibition of cellular growth (Kirschenbaum et al, 2001); all occur at least partly through inhibition of the cyclooxygenase (COX) enzymes involved in prostaglandin synthesis.…”

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confidence: 99%

Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis

2004

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Animal and laboratory studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. To assess this association, we conducted a systematic review and meta-analysis of observational studies published before January 2003. We derived summary odds ratios (ORs) using both fixed and random effects models and performed subgroup analyses to explore the possible sources of heterogeneity between combined studies. We identified 12 reports (five retrospective and seven prospective studies). Most studies of aspirin use reported inverse associations, but only two were statistically significant. The summary OR for the association between aspirin use and prostate cancer was 0.9 (95% confidence interval: 0.82 -0.99; test of homogeneity P ¼ 0.32), and varied from 1.0 for retrospective studies to 0.85 for prospective studies. Studies that measured exposure to a mixture of NSAIDs were less consistent. These results indicate an inverse association between aspirin use and prostate cancer risk. The current epidemiological evidence and, in particular, the strong and consistent laboratory evidence underline the need for additional epidemiological studies to confirm the direction and magnitude of the association.

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“…To increase effectiveness, synthetic receptor-selective retinoids have been developed (14,28,50,(57)(58)(59)(60)(61)(62)(63)(64)(65). Various biomarkers were applied to determine the optimal end point of chemoprophylactic treatment (16,18,19,29,45,50,60,90,94,(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109).…”

Section: Discussionmentioning

confidence: 99%

“…To determine a preliminary endpoint, genetic, cellular, biochemical or immunological surrogate biomarkers are being used and validated so that chemoprevention can be evaluated before a recurrence becomes evident. This requires an understanding of the biology of carcinogenesis to find biomarkers which reveal particular steps in tumor development (16,18,19,29,45,50,90,94,(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109). The demonstration of RARβ (as an mRNA or as a protein in immunohistochemistry) was used in some studies as a sensitive biomarker for chemoprevention (13,17,18,84,88,89,95).…”

Section: Introductionmentioning

confidence: 99%