Morphological Changes in the Lingual Papillae and Their Connective Tissue Cores on the 7,12-dimethylbenz[.ALPHA.]anthracene (DMBA) stimulated Rat Experimental Model

Zheng, Junhua; Xie, Liping; He, Ting; Liu, Shilong; Yoshimura, Ken; Kageyama, Ikuo; Kobayashi, Kan

doi:10.2535/ofaj.85.129

Cited by 2 publications

(3 citation statements)

References 25 publications

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“…The transformation of normal cells into malignant ones is mediated by disorders in several cell cycle regulating agents, whether positive or negative. Cell cycle progression is positively regulated by multiple cyclins and cyclin-dependent kinases, and negatively by a number of cyclin-dependent kinase inhibitors 6 . Ki-67 is a nuclear protein expressed in all phases of the cell cycle (G1, S, G2 and M), which, however, is absent in the G0 phase ("resting phase").…”

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confidence: 99%

Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

Alves

Ribeiro

Lima

et al. 2016

Rev. Col. Bras. Cir.

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Objective: to evaluate the influence of INK4a proteins immunohistochemical expressions on the clinical and morphological parameters of perioral squamous cell carcinoma induced with 9,10-dimethyl-1,2-benzanthracene (DMBA) in mice. Methods: we topically induced the lesions in the oral commissure of ten Swiss mice for 20 weeks, determining the time to tumors onset and the average tumor volume up to 26 weeks. In histopathological analysis, the variables studied were histological malignancy grade and the immunohistochemical expression of INK4a proteins. The correlation between variables was determined by application of the Spearman correlation test. Results: the mean time to onset of perioral lesions was 21.1 ± 2.13 weeks; mean tumor volume was 555.91 ± 205.52 mm3. Of the induced tumors, 80% were classified as low score and 20% high score. There was diffuse positivity for Ki-67 in 100% of lesions -Proliferation Index (PI) of 50.1 ± 18.0. There was a strong direct correlation between Ki-67 immunoreactivity and tumor volume (R = 0.702) and a low correlation with the malignancy score (R = 0.486). The P16INK4a protein expression was heterogeneous, showing a weak correlation with tumor volume (R = 0.334). There was no correlation between the immunohistochemical expression of the two proteins studied. Conclusion: in an experimental model of DMBA-induced perioral carcinogenesis, tumor progression was associated with the tumor proliferative fraction (Ki-67 positive cells) and with tumor histological grading, but not with P16 INK4a expression.Keywords: Carcinogenesis. 9,10-Dimetil-1,2-benzanthracene. Immunohistochemistry. Ki-67 Antigen. Genes, p16. MTSI, CDK4I or CDKN2) located on chromosome 9p, locus 21, involved in cell cycle progression blocking process. It is inactive in a wide range human malignancies. The loss of p16 INK4a immunoexpression has been observed in the early stages of oral carcinogenesis and has been considered a molecular event of significant value in the prognostic analysis of such tumors 9,10 . This study evaluated the influence of Ki-67 and p16 proteins immunohistochemical expression on morphological parameters (mean tumor volume and histological malignancy grade) of DMBA-induced perioral SCC in mice. In addition, it sought to verify the existence of correlation between the immunoreactivity of p16 and Ki-67 proteins. METHODSThe development of the study had the approval of the Ethics in Research Committee of the Universidade Tiradentes -Aracaju / SE, with protocol number 191208. Animals and chemical carcinogenesis induction procedureWe used ten Swiss mice without distinction between gender, from the vivarium of the Universidade Tiradentes, with a body mass of about 150 ± 30g (Average age 100 days).We induced the oral lesions in the mice left oral commissure by the topical application of 9,10-dimethyl-1,2-benzanthracene (DMBA), diluted to 0.5% in acetone, on a weekly basis in three alternate days for 20 weeks 11 . After this period, the animals were kept under observation for six weeks, and we duly regis...

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confidence: 99%

Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

Alves

Ribeiro

Lima

et al. 2016

Rev. Col. Bras. Cir.

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“…To create an orthotopic tongue cancer model, a 1.5% DMBA acetone solution (Sigma-Aldrich, St. Louis, MO, USA) was applied to the left margin of the anterior tongue in a scratched area, three times a week, and hamsters were fasted for 2 h after applying DMBA to avoid damage produced by DMBA to the other alimentary structures other than the tongue according to a previously published method by Fujita et al ( 24 ), until a tumor was formed in the tongue (~8 weeks). Eight weeks after DMBA application (tumor diameter, 3~4 mm), the tongue cancer grew rapidly ( 23 , 25 ) and treatment began. The carboplatin injection was purchased from Qilu Pharmaceutical Co., Ltd. (Jinan, China) and diluted with 0.9% sodium chloride solution to the appropriate concentration for injection.…”

Section: Methodsmentioning

confidence: 99%

“…Chemically-induced orthotopic models are commonly used for the preclinical and translational studies of compounds and therapies because they mimic many aspects of human diseases, provide reproducible results and allow evaluation of the systemic effects of treatments. Our research team previously demonstrated that hamster tongue mucosa underwent gradual changes from hyperplasia, carcinoma in situ to early invasive carcinoma, when exposed to 7,12-dimethylbenz(alpha)anthracene (DMBA) ( 22 , 23 ). The pathogenesis of this tongue cancer model is similar to human tongue carcinoma.…”

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confidence: 99%

Effects of low-intensity ultrasound combined with low-dose carboplatin in an orthotopic hamster model of tongue cancer: A preclinical study

Jin

et al. 2018

Oncol Rep

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Low-intensity ultrasound (LIUS) combined with chemotherapy is an innovative modality for cancer treatment, but its effect on orthotopic carcinoma remains unknown. Our previous study revealed that LIUS enhanced the growth inhibitory effects of several chemotherapeutic drugs in nude mice with transplanted tumors. In the present study, we used 7,12-dimethylbenz(alpha)anthracene to induce orthotopic tongue carcinogenesis in hamsters. We used the first-line chemotherapy drug for tongue cancer, carboplatin (CBP) in combination with LIUS to investigate the synergistic effect. The results revealed that LIUS combined with low-dose CBP enhanced the inhibitory effects of CBP on tumor growth, prolonged survival, and did not increase the incidence of side-effects. It also enhanced the inherent DNA damage caused by CBP, suppressed the expression of the DNA repair proteins O6-methylguanine DNA methyltransferase (MGMT) and Chk1, and increased the expression of DNA damage-inducible protein GADD45α. Furthermore, compared with CBP alone, LIUS combined with CBP reduced the expression of cyclin D1 and cyclin B1, induced the expression of caspase-3, cleaved caspase-3, caspase-8, Bax, and Bak, and inhibited the expression of Bcl-2. Examination of clinical samples revealed that MGMT, Chk1, and Gadd45α were higher in OTSCC than in adjacent normal tissue. Hence, our results indicated that LIUS enhanced the ability of low-dose CBP to damage DNA in an orthotopic hamster model of tongue cancer, induced apoptosis, inhibited tumor growth and progression, while it did not increase the toxic side-effects of the drug, suggesting additional clinical benefits for patients treated with the combination of CBP with LIUS.

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Morphological Changes in the Lingual Papillae and Their Connective Tissue Cores on the 7,12-dimethylbenz[.ALPHA.]anthracene (DMBA) stimulated Rat Experimental Model

Cited by 2 publications

References 25 publications

Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

Effects of low-intensity ultrasound combined with low-dose carboplatin in an orthotopic hamster model of tongue cancer: A preclinical study

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