Comparison of injectable doxorubicin & its nanodrug complex chemotherapy for the treatment of 4-nitroquinoline-1-oxide induced oral squamous cell carcinoma in rats.

BACKGROUND & OBJECTIVES: Combination treatments of chemotherapy and nanoparticle drug delivery have shown significant promise in cancer treatment. The aim of the present study was to compare the efficacy of a nanodrug complex with its free form in the treatment of tongue squamous cell carcinoma induced by 4-nitroquinoline-1-oxide in rats. METHODS: In this study, 75 male Sprague-Dawley rats were divided into five groups. Oral squamous cell carcinoma (OSCC) was induced by using 4- nitroquinoline-1-oxide (4NQO) as a carcinogen. Newly formulated doxorubicin (DOX)-methotrexate (MTX)-loaded nanoparticles, and free DOX-MTX were administrated intravenously to rats. During the study, the animals were weighed once a week. At the end of the treatment, rats' tongues were evaluated histopathologically. RESULTS: There was significant difference between the mean weight of rats in groups A and B (P=0.001) and also groups A and K (P<0.001). No significant association was found between the mortality rate of groups. The difference between the severity of dysplasia of treated and untreated groups was significant (P<0.001). INTERPRETATION & CONCLUSIONS: Our study showed that DOX-MTX nanoparticle complex was more effective than free DOX-MTX in chemotherapy treatment of oral squamous cell carcinoma in rat models. Further investigations are necessary to clarify the advantages and disadvantages of the nanoparticle complex and its potential therapeutic application for different types of cancer.

DOX-MTX-NPs augment p53 mRNA expression in OSCC model in rat: effects of IV and oral routes.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Cancer development and progression require inactivation of tumor suppressor genes and activation of proto-oncogenes. The well recognized mechanism of action demonstrated for chemotherapeutic agents is induction of apoptosis via reactivation of p53. In this context, we evaluate the efficacy of IV and oral routes of our novel PH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting p53 profile in an OSCC rat model. METHODS: In this study, 120 male rats were divided into 8 groups of 15 animals each. The new formulated DOX-MTX NP and free doxorubicin were IV and orally given to rats with 4-nitroquinoline-1- oxide induced OSCC. RESULTS: RESULTS showed that both DOX and DOX-MTX-NP caused significant increase in mRNA levels of P53 compared to the untreated group (p<0.000). With both DOX and DOX-MTX NP, the IV mode was more effective than the oral (gavage) route (p<0.000). Surprisingly, in oral mode, p53 mRNA was not affected in DOX treated groups (p>0.05), Nonetheless, both IV and oral administration of MTX-DOX NP showed superior activity (~3 fold) over free DOX in reactivation of p53 in OSCC (p<0.000). The effectiveness of oral route in group treated with nanodrug accounts for the enhanced bioavailability of nanoparticulated DOX- MTX compared to free DOX. Moreover, in treated groups, tumor stage was markedly related to the amount of p53 mRNA (p<0.05). CONCLUSION: Both oral and IV application of our novel nanodrug possesses superior activity over free DOX-in up-regulation of p53 in a OSCC model and this increase in p53 level associated with less aggressive tumors in our study. Although, impressive results obtained with IV form of nanodrug (-21 fold increase in p53 mRNA level) but both forms of nanodrug are effective in OSCC, with less toxicity normal cells.

Oral and IV dosages of doxorubicin-methotrexate loaded- nanoparticles inhibit progression of oral cancer by down- regulation of matrix Methaloproteinase 2 expression in vivo.

Oral cancer is one of the most common and lethal cancers in the world. Combination chemotherapy coupled with nanoparticle drug delivery holds substantial promise in cancer therapy. This study aimed to evaluate the efficacy and safety of two dosages of our novel pH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NPs) with attention to the MMP-2 mRNA profile in a 4-nitroquinoline-1-oxide induced oral squamous cell carcinoma (OSCC) model in the rat. Our results showed that both IV and oral dosages of DOX-MTX NP caused significant decrease in mRNA levels of MMP-2 compared to the untreated group (p<0.003). Surprisingly, MMP-2 mRNA was not affected in DOX treated compared to cancer group (p>0.05). Our results indicated that IV dosage of MTX-DOX is more effective than free DOX (12 fold) in inhibiting the activity of MMP-2 in OSCCs (P<0.001). Furthermore, MMP-2 mRNA expression in the DOX-MTX treated group showed a significant relation with histopathological changes (P=0.011). Compared to the untreated cancer group, we observed no pathological changes and neither a significant alteration in MMP-2 amount in either of healthy controls that were treated with oral and IV dosages of DOX-MTX NPs whilst cancer group showed a high level of MMP-2 expression compared to healthy controls (p<0.001).Taking together our results indicate that DOX- MTX NPs is a safe chemotherapeutic nanodrug that its oral and IV forms possess potent anti-cancer properties on aggressive tumors like OSCC, possibly by affecting the expression of genes that drive tumor invasion and metastasis.

Immunohistochemical expression of Src protein in peripheral and central giant cell granulomas of the jaws.

AIM AND OBJECTIVE: The aim of this study was to investigate the expression of Src protein (an osteoclastic factor) in peripheral and central giant cell granulomas (PGCG and CGCGs) of the jaws and the relationship between the expression of this protein and the clinical behavior of these two lesions. MATERIALS AND METHODS: Thirty cases of PGCG and 30 cases of CGCG were immunohistochemically stained with Src. A staining-intensity-distribution (SID) score (proportion of stained cells × staining intensity) was used to evaluate immunoreactivity of the protein. Data were analyzed using statistical package for social sciences (SPSS) 17.0. RESULTS: There were no significant differences in the Src expression and the SID score between PGCG and CGCG. Furthermore, Spearman's rank correlation coefficient showed that there was a significant correlation between Src expression and SID score within both PGCG and CGCG (P < 0.001; r = 0.87 and 0.75, respectively). CONCLUSION: The findings of this study suggest that the multinucleated giant cells share some similarities with osteoclasts and Src protein can be used as a new therapeutic target to inhibit osteoclastic activity. In addition, differences in immunoreactivity of this osteoclastic protein do not reflect different clinical behaviors of PGCG and CGCG.

Immunohistochemical correlation of epidermal growth factor receptor and c-erbB-2 with histopathologic grading of mucoepidermoid carcinoma.

OBJECTIVE: Mucoepidermoid carcinoma is the most common salivary gland malignancy with highly variable biologic potential that correlates with the histopathologic grade of the tumor. Therefore, identification of the histopathologic grade of the mucoepidermoid carcinoma is very important in the treatment and determination of the final prognosis. The present study was performed to survey immunohistochemically Epidermal Growth Factor ReceptorEGFR and c-erbB-2 expression in different grades of mucoepidermoid carcinoma. MATERIALS AND METHODS: This retrospective study included 46 formalin-fixed, paraffin-embedded blocks of mucoepidermoid carcinoma. Based on histopathologic parameters, samples were classified into three grades. Then new sections were made and stained by immunohistochemistry (IHC) method for EGFR and c-erbB-2. Finally, EGFR and c-erbB-2 expression and their correlation with histopathologic grading were statistically analyzed by ANOVA. Nineteen samples of normal salivary gland tissue were also chosen as control group. RESULTS: The means of EGFR and c-erbB-2 were 71%, 71%, respectively. Statistically significant correlation was found between EGFR expression and histopathologic grading of mucoepidermoid carcinoma of salivary glands (P < 0.001). There was no statistically significant correlation between histopathologic grading of salivary gland mucoepidermoid carcinoma and c-erbB-2 expression (P = 0.60). CONCLUSION: There is a parallelism between an increase in EGFR expression and increase in the histopathologic grading of salivary gland mucoepidermoid carcinoma. Therefore, the biologic behavior of salivary gland mucoepidermoid carcinoma can be determined by EGFR expression and it is a useful technique for determination of tumor grades and probably their prognosis.

Diagnostic value of silver nitrate staining for nucleolar organizer regions in selected head and neck tumors.

BACKGROUND: The present study is aimed to assess the usefulness of silver nitrate staining of nucleolar organizer regions (NORs) as a quantitative criterion for the diagnosis of selected head and neck tumors. MATERIALS AND METHODS: The silver nitrate staining technique was used on 195 paraffin blocks collected from 85 patients. The samples consisted of 21 squamous cell carcinoma (SCC) of larynx, 28 SCC of oral mucosa and 36 samples of most common salivary gland tumors. Mann-Whitney U-Test was used for data analysis. RESULTS: A significant difference was seen in the number of AgNOR dots between oral and laryngeal SCC with surrounding dysplastic and normal tissues (P < 0.001) and also between mucoepidermoid carcinoma and adenoid cystic carcinoma with pleomorphic adenoma and normal salivary gland tissue (P < 0.001). CONCLUSION: The silver nitrate staining for NORs is a useful method for aiding the diagnosis of malignant and dysplastic mucosal lesions and also malignant and benign salivary gland tumors.