الفهرس 
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Abstract
Breast cancer is considered the second most common cancer in the world accounting for 22.9% and 37.7% of all female cancers worldwide and in Egypt, respectively. In addition, breast cancer accounts for 16% of all cancer deaths among women globally, according to the World Health Organization (WHO).
Phytochemical prevention for severe health problems has recently gained scientific recognition worldwide. Moreover, studies on the pharmacological mechanisms and chemical structures of herbal extracts had caught great interest regarding their anti-cancer activity.
The aim of the current work was to investigate apoptotic, necrotic and anti-proliferative effects of metformin and graviola on experimentally mammary tumor induced in Swiss albino mice. In order to evaluate the efficacy of the studied groups, the following investigations were done:
1- Measurement of glutathione-S-transferase activity (GST), glutathione peroxidase activity (GPx), super oxide dismutase activity (SOD) catalase activity (Cat), total antioxidant activity (TAC) and malondialdehyde (MDA).
2- Measurement the serum levels of ALT, AST, ALP, total protein, albumin, urea and creatinine were measured to detect the effect of graviola and metformin on liver and kidney functions.
3- Measurement of vascular endothelial growth factor (VEGF) by ELISA
4- Measurement of survivin by ELISA
5- Evaluation of the structural changes induced by different treatment in tumor tissue using H&E, Feulgen and Masson’s Trichrome stains by microscope.
The experimental results showed that:
1- Increase in lipid peroxidation was reported in controlled group which carried EAC. A significant increase in the levels of MDA was observed in all EAC bearing groups. Animals in (graviola only) treated group exhibited significantly low levels of MDA, followed by (metformin only) treated group and the lowest MDA level was in (metformin and graviola) treated group, as compared with the control group.
2- Implanted mice with EAC showed decreased activities of antioxidants (SOD, CAT, GR, GPx, and TAC). On the other hand, there is a significant increase in the enzymatic and non-enzymatic antioxidant guard in (graviola only) treated group, followed by (metformin only) treated group and the highest antioxidant levels was in (metformin and graviola) treated group when compared with control group.
3- The EAC caused a significant increase in the serum urea and creatinine levels in the studied groups. On the other hand (graviola only) treated group exhibited significantly low levels of serum creatinine and urea, followed by (metformin only) treated group and the lowest serum creatinine and urea levels was in (metformin and graviola) treated group which is probably an indication of protection against renal toxicity.
The EAC caused a significant increase in the serum activities of ALT, AST, ALP, GGT, total protein and albumin of the EAC tumor treated groups. However, in the EAC treated groups with (graviola only) exhibited significantly low levels of serum ALT, AST, ALP, GGT, total protein and albumin, followed by (metformin only) treated group and the lowest serum ALT, AST, ALP, GGT, total protein and albumin levels was in (metformin and graviola) treated group which is an indication of the hepato-protection against hepatotoxicity.
5- Increase in vascular endothelial growth factor was reported in controlled group which carried EAC. A significant increase in the levels of VEGF was observed in all EAC bearing groups. Animals in (graviola only) treated group exhibited significantly low levels of VEGF, followed by (metformin only) treated group and the lowest VEGF level was in (metformin and graviola) treated group, as compared with the control group.
6- In the present study, the increase in survivin was reported in controlled group which carried EAC. A significant increase in the levels of survivin was observed in all EAC bearing groups. Animals in (graviola only) treated group exhibited significantly low levels of survivin, followed by (metformin only) treated group and the lowest survivin level was in (metformin and graviola) treated group, as compared with the control group.
7- The data in the present study showed that during the whole course of experiment the histopathological changes were synchronized with the biochemical changes.
8- Histological evaluation by hematoxylin and eosin dyes (H&E) revealed that graviola and metformin induced apoptosis, necrosis and also have anti-proliferative effects as illustrated above especially in combination group (mixture of metformin and graviola).
In addition, reduction of malignant tumor cells thickness, metastasis and angiogenesis was observed.
9- The histochemical examination of mammary tumor sections stained with Feulgen Stain showed less DNA content in the positive control group (EAC) and significant variation in both size and shape due to malignancy and mutation occurred after injection with EAC, while after treatment with both graviola & metformin showed significant decrease in DNA content with slight variation in size and shape of DNA as response to treatment.
10- The histochemical examination of mammary tumor sections stained with Masson‟s trichrome stain for collagen of showed malignant neoplastic cells with low collagen deposition within the Ehrlich group (positive control), while increased collagen content after using graviola and metformin was due to the inhibition of endothelial cells migration.
11- All the previous histological findings revealed significant response to graviola and metformin.