الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is one of the most prevalent cancers among women and the second leading cause of death worldwide. Although the etiology of breast cancer is not well known, several risk factors have been suggested to have an influence on the development of this malignant tumor. Genetic, epigenetic, hormonal and environmental factors are contributing to the development of this disease. The treatment of breast cancer is very complex and includes the combination of surgery, chemotherapy, radiotherapy, hormonal therapy or immunotherapy.
Despite the advances in multimodal adjuvant and neoadjuvant therapies, the management of breast cancer remains a significant problem. This has increased the necessity for extensive research to find new agents for the treatment of breast cancer other than the well known cytotoxic agents in a trial to get better effect with better tolerated side effects.
Due to the importance of epigenetics in the initiation and progression of breast cancer; our study was designed to investigate the effect of valproic acid (a histone deacetylase inhibitor) as a one of the epigenetic drugs on the growth and proliferation of mammary carcinoma induced in female rats. In addition, the present work was also set to detect the efficacy of two other drugs with potential antitumor effect which are melatonin and vitamin D3.
Moreover, the current work was also meant to compare between the efficacies of these probed drugs, and to investigate the possible mechanisms of action of all used drugs to achieve best therapeutic management of breast cancer.
Fifty female albino rats weighing between (110 to 130 g) were used in the current study. Ten rats were allowed to feed normal diet and received only 1 ml of sesame oil orally to serve as plain normal control. The other forty rats were subjected to the induction of mammary carcinoma by administering a single dose of 20mg of dimethylbenz(α)anthracene (DMBA) suspended in 1 ml of sesame oil/rat via an oral gavage syringe. Starting from the 5 th week after DMBA intubation, rats were palpated once weekly to assess the appearance of mammary tumors which took 7-16 months to appear and to reach a considerable size. The rats were randomly assigned to four experimental groups (each of 10 rats) as follows:
Group I: DMBA-treated group; rats received only 1ml propylene glycol/day; (the vehicle used for suspending the drugs) orally to serve as a control for the other treated animals.
Group II: Valproic acid - treated group; rats received valproic acid 300 mg/kg/day orally.
Group III: Melatonin-treated group; rats received melatonin 10 mg/kg/day orally.
Group IV: Vitamin D3 -treated group; rats received vitamin D3 7 μg/kg/week divided into two doses orally.
All the probed drugs were dissolved or suspended in 1ml propylene glycol. So that, a total volume of 1ml propylene glycol contained the required dose of the drugs per kg were given for a treatment period of consecutive 28 days. Tumor volumes were measured at the start of the treatment and at weekly intervals during the treatment period to assess the effect of different drugs on the rate of tumor growth. At the end of the experimentation period and after an overnight fast, blood samples were collected from the retro orbital venous plexus of the rat. Serum samples were separated and used for estimation of aromatase enzyme activity. Animals were then sacrificed, tumors were excised and tissue sections were prepared for determination of aromatase enzyme concentration by Enzyme Linked Immunosorbent Assay (ELISA), and immunohistochemical detection of estrogen receptors (ER) and ki-67 (proliferation marker) expression. Tumor tissues were also used for quantitative determination of caspase-3 by ELISA and for histopathological (H & E) examination.
Livers were also isolated, homogenized using the specific homogenizing solution and used for determination of malondialdehyde (MDA) and reduced glutathione (GSH) concentration.
Results of the present work revealed that the untreated DMBA-induced mammary carcinoma-bearing rats had a marked, progressive increase in tumor volume along the course of the experiment. Treatment with valproic acid, melatonin or cholecalciferol significantly decreased the rate of mammary tumor growth throughout the period of the experiment as compared to the untreated DMBA-induced mammary carcinoma-bearing rats. Moreover, valproic acid showed a significant decrease in tumor volume at the end of the experiment relevant to the starting volume.
Furthermore, results of the present study demonstrated that valproic acid produced the most favorable response on the rate of mammary tumor growth among all the studied groups. Its antitumor effect was elicited through a decrease in aromatase enzyme concentration, re-expresion of ER, inhibition of tumor cell proliferation, induction of apoptosis, lipid peroxidation lowering effect and antioxidant effect.
Melatonin was the second drug following valproic acid in reducing the rate of mammary tumor growth with no significant difference between both drugs. Melatonin treatment was associated with antiestrogenic effect manifested by the marked loss of ER expression and the decrease in estrogen synthesis through the decrease in aromatase enzyme concentration. Melatonin has also shown a marked antiproliferative, proapoptotic, and lipid peroxidation- lowering and antioxidant effects.
The significant reduction in the rate of breast cancer growth obtained by cholecalciferol therapy was attributed to: its ability to inhibit the synthesis of estrogens and down-regulate the expression of ER. Cholecalciferol treatment was also associated with significant tumor cell cytostasis, induction of apoptosis and potential antioxidant effect together with a significant decrease in lipid peroxidation.
Taken together, this work provided evidence that each of valproic acid, melatonin and vitamin D3 exerted antitumor effect on breast cancer induced in rats via numerous mechanisms of actions.