ABT-510 Is an Effective Chemopreventive Agent in the Mouse 4-Nitroquinoline 1-Oxide Model of Oral Carcinogenesis
| Autor: | Kristen Kasza, Asif Jalil, Mark W. Lingen, Rifat Hasina, Colleen L. Jones, Leslie E. Martin |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cancer Research Pathology medicine.medical_specialty Hyperkeratoses Angiogenesis Angiogenesis Inhibitors Biology medicine.disease_cause Article Mice chemistry.chemical_compound medicine Animals Survival rate Mouth neoplasm Neovascularization Pathologic medicine.disease Immunohistochemistry 4-Nitroquinoline-1-oxide Vascular endothelial growth factor Disease Models Animal stomatognathic diseases Vascular endothelial growth factor A Ki-67 Antigen Oncology chemistry Dysplasia Microvessels Carcinogens Carcinoma Squamous Cell Mice Inbred CBA Cancer research Mouth Neoplasms Carcinogenesis Oligopeptides Precancerous Conditions |
| Zdroj: | Cancer Prevention Research. 2:385-393 |
| ISSN: | 1940-6215 1940-6207 |
| DOI: | 10.1158/1940-6207.capr-08-0211 |
| Popis: | Despite numerous advances, the 5-year survival rate for head and neck squamous cell cancer (HNSCC) has remained largely unchanged. This poor outcome is due to several variables, including the development of multiple primary tumors. Therefore, it is essential to supplement early detection with preventive strategies. Using the 4-nitroquinoline 1-oxide (4-NQO) mouse model, we sought to define an appropriate dose and duration of administration that would predict the histologic timeline of HNSCC progression. Additionally, we sought to determine the timing of the onset of the angiogenic phenotype. Finally, using ABT-510 as a proof-of-principle drug, we tested the hypothesis that inhibitors of angiogenesis can slow/delay the development of HNSCC. We determined that 8 weeks of 100 μg/mL 4-NQO in the drinking water was the optimal dosage and duration to cause a sufficient incidence of hyperkeratoses, dysplasias, and HNSCC over a period of 32 weeks with minimal morbidity and mortality. Increased microvessel density and vascular endothelial growth factor expression in hyperkeratotic lesions provided evidence that the initiation of the angiogenic phenotype occurred before the development of dysplasia. Importantly, ABT-510 significantly decreased the overall incidence of HNSCC from 37.3% to 20.3% (P = 0.021) as well as the combined incidence of dysplasia and HNSCC from 82.7% to 50.6% (P < 0.001). These findings suggest that our refinement of the 4-NQO model allows for the investigation of the histologic, molecular, and biological alterations that occur during the premalignant phase of HNSCC. In addition, these data support the hypothesis that inhibitors of angiogenesis may be promising chemopreventive agents. |
| Databáze: | OpenAIRE |
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