Gimenez-Conti, Irma B. D.D.S., Ph.D.
Selected Publications | Search PubMed | ContactResearch Interests
Modulation of tumor progression, chemopreventive agents, intermediate biomarkers
Current Research
The goal of my research is to study the tumor biology and carcinogenesis of oral cancer using the hamster cheek model. We are also using this model to test the efficacy of chemopreventive agents and to study their possible mechanisms of action in order to select agents that may be useful in human oral cancer intervention studies.
Oral cancer, mainly squamous cell carcinomas (SCC), is the sixth most frequent cancer in the world and accounts for 2-6% of all malignancies. The etiology of this cancer has been linked to environmental factors and epidemiological studies strongly suggest a role of chemical carcinogenesis. Excessive use of tobacco and alcohol are possible etiologic factors that may induce SCC in the oral mucosa and larynx. The hamster cheek pouch model has been shown to mimic the carcinogenesis of human oral mucosa, not only from the histopathological point of view, but also at the molecular level. Further, this model has been extensively used to test chemopreventive compounds in an effort to develop cancer preventive strategies for the human upper aerodigestive tract.
My laboratory has studied this model from different angles. We have better characterized the chemically induced lesions in this model, and we have characterized two different subtypes of tumors, endophytic and exophytic SCC’s. We have also, for the first time, shown that mutations in the H-ras are frequent in these SCC’s, particularly in those that start as exophytic tumors. We have also showen the presence of over-expression and mutations in the p53 gene as well as over-expression of TGF B1 and EGF-R. Studies in this model have been limited to the use of DMBA as the carcinogenic agent and previous attempts to broaden the use of this model to other carcinogenic compounds that better represent environmental carcinogens have not been successful. We have been able to develop a protocol of carcinogenesis in the hamster cheek pouch using B[a]P, a widely distributed carcinogenic chemical in the environment, formed as a by-product of the combustion of organic materials and cigarette smoke. Tumors induced in the hamster cheek pouch with B[a]P are endophytic squamous cell carcinomas (SCC) that closely resemble SCC’s of the human oral mucosa. Furthermore, we have also observed typical pre-malignant lesions equivalent to human leukoplakias.
As discussed above, the other major interest of my laboratory is the use of the hamster cheek pouch in chemoprevention studies. We have determined the efficacy of curcumin and green tea polyphenols (antioxidants), Celecoxib (Cox 2 inhibitor) and 4-HPR (synthetic retinoid), utilizing short-term mechanistic end points such as cellular proliferation assessed by immunohistochemical analyses of bromodeoxyuridine (Brdu), accumulation of p53 protein and apoptosis.
From these studies we concluded that that curcumin and Celecoxib might have a plausible chemopreventive effect on oral carcinogenesis. Tumor experiments using curcumin and Celecoxib were evaluated at two time points; 20 weeks and 32 weeks of treatment. At 20 weeks, both compounds showed a reduced incidence of leukoplakia-like lesions, carcinomas in situ and SCC, as well as a decrease in proliferation, and p53 protein accumulation, and a significant increase in apoptotic cells. In contrast, after 32 weeks of treatment, curcumin did not decrease the number of tumors and Celecoxib showed an increase in the number of tumors in the B[a]P-treated hamsters. It was concluded that curcumin could act as an anti-inflammatory agent up to 20 weeks reducing leukoplakia-like lesions, but the true neoplastic lesions progress to SCC. In the case of Celecoxib, the tween/PEG used as the vehicle could also act as a promoter increasing the number of tumors.
We also examined the putative chemopreventive effects of clotrimazole on the hamster cheek pouch carcinogenesis model. Clotrimazole is a widely used synthetic antimycotic. Recently, it became clear that clotrimazole has anti-proliferative effects. We examined the long-term chemopreventive effects of clotrimazole on the hamster cheek pouch carcinogenesis model. The right cheek pouch of each male Syrian Hamster was treated topically 3 times per week with 50mM clotrimazole followed 30 minutes later by 2% B[a]P. The animals were sacrificed at 32-weeks and the right cheek pouches were harvested for histological and immunohistochemical evaluation. Upon histological evaluation the lesions were classified as pre-cancerous lesions, carcinomas in situ, or squamous cell carcinomas. A very significant decrease (~80%) in tumor incidence was observed in clotrimazole-treated animals, when compared to the B[a]P-treated positive control group. Moreover, there was a significant decrease in pre-cancerous lesions (30%) and carcinomas in situ (55%) when compared with the control. Clotrimazole-treated animals also demonstrated a significant decrease in proliferation (40%), p53 expression (58%) and CD1 expression (57%), compared to the positive control group. These results indicate significant chemopreventive activity of clotrimazole in the B[a]P-induced carcinogenesis in the hamster cheek pouch model.
The experiments described above have identified potential chemopreventive agents in the model and have also allowed us to narrow down possible doses. They have also given some indication of the possible mechanisms of action. Based on this information we have designed experiments to test the effect of Clotrimazole in already established pre-malignant lesion experiments using both pre-malignant and malignant lesions as endpoints.
Selected Publications
- Gimenez-Conti I, Woodhead AD, Harshbarger JC, Kazianis S, Setlow RB, Nairn RS, Walter RB. A proposed classification scheme for Xiphophorus melanomas based on histopathologic analyses, Mar Biotechnol (NY), 3 (Supplement 1), S100-6, 2001
- Coghlan L, Utzinger U, Richards-Kortum R, Brookner C, Zuluaga A, Gimenez-Conti I, Follen M. Fluorescence spectroscopy of epithelial tissue throughout the dysplasia- carcinoma sequence in an animal model: Spectroscopic changes precede morphologic changes, Lasers Surg Med, 29 (1), 1-10, 2001
- Coghlan L, Utzinger U, Drezek R, Heintzelman D, Zuluaga A, Brookner C, Gimenez-Conti, I, Richards-Kortum R, Follen M. Optimal excitation wavelengths for detection of squamous intra-epithelial neoplasia: results from an animal model, Optics Express 7:436-446, 2000
- Xu J, Gimenez-Conti IB, Cunningham JE, Collet AM, Luna MA, Lanfranchi HE, Spitz MR, Conti CJ. Alterations of p53, cyclin D1, Rb, and H-ras in human oral carcinomas related to tobacco use, Cancer, 83 (2), 204-12, 1998
- Gimenez-Conti IB, LaBate ME, Liu F, Osterndorff EA. p53 alterations in chemically induced hamster cheek-pouch lesions, Mol Carcinog, 16 (4), 197-202, 1996
Contact Information
Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9577