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The present study, was carried out to evaluate the role of chitosan nanoparticles as a drug carrier for 5-fluorouracil and to evaluate the anticancer activity of 5FUCNPs either alone or in combined with γ-radiation . As tumor have systemic effects on the host , the antioxidant status for tumor , liver, kidney and spleen have been studied .More and above , histopathological and apoptotic examination of tumor , liver , kidney and spleen tissues were performed to evaluate the histo-pathological and apoptotic changes.
In vitro the cytotoxicity of nanoparticles not only led to the death of Ehrlich carcinoma cells, but also led to the burst of these dead cells at certain doses. Nanoparticles led to rupture of cells content after their death .The median lethal concentration of 5FUCNPs was 20μg/ml for Ehrlich carcinoma cells.
In vivo experiments were performed on healthy Ehrlich-bearing female Swiss albino mice. Mice were randomly assigned and equally divided into 5 experimental
groups each of 10 mice as follows : control group : the mice were neither treated nor irradiated . Tumor-bearing group: each mouse in this group was inoculated
subcutaneously with 0.2 ml of EAC cells (2.5x106 cells) for solid tumor induction .The animals were left without any treatment till the end of the experiment. Tumor bearing- 5FUCNPs group: Mice in this group were orally treated with 5FUCNPs (0.5 mg/kg b.wt.) daily, for 15 successive days from the 7th days after inoculation of EAC. Tumor-Irradiated group: Each mouse in this group was inoculated subcutaneously with EAC cells and each tumor-bearing mouse was exposed to γ-radiation (0.25Gy x 2/week) for two weeks. Tumor bearing-5FUCNPs-Irradiated group: in this group mice bearing solid tumor was orally supplemented with 5FUCNPs and exposed to γ-radiation ( 0.25 Gy x 2/week) for two weeks.
The results obtained can be summarized as following
Studying the systemic effects of the tumor on the host showed that,the presence of tumor resulted in imbalance of the antioxidant defense system including
decrease in GSH content and increase in LPO content in liver , kidney and spleen tissues.
Treatment of mice bearing tumor with 5FUCNPs induced tumor growth regression by decreasing the level of angiogenic factors (TNF- α, PDGF and VEGF) and increasing LPO content in the tumor tissue.
The histopathological examination of the tumor tissue recorded that treatment of female mice bearing Ehrlich carcinoma with 5FUCNPs and or low doses of γ-irradiation showed great destruction of tumor tissue cells.
Also, apoptotic and necrotic examination recorded that treatment of female mice bearing Ehrlich carcinoma with 5FUCNPs and or low doses of γ-irrradiation represented necrotic regions and vaculated areas.
Treatment of the experimental mice-bearing solid Ehrlich tumor with 5FUCNPs and or low doses of γ-irradiation revealed a decrease in LPO and increase in GSH contents of liver , kidney and spleen in compared to EC-bearing group.
The histopathological Examination of liver sections of mice bearing Ehrlich carcinoma showed accumulation of Ehrlich carcinoma cells (ECs) around congested portal blood vessels with completely haemolysed red blood cells (RBCs) in the portal vein . On the other hand , treatment of the experimental mice-bearing solid Ehrlich tumor with 5FUCNPs and or low doses of γ-irradiation revealed great disappearance of metastatic Ehrlich carcinoma cells. Great dilatation and wideness of the central vein was observed and disappearance of metastatic Ehrlich carcinoma cells was also observed in the liver of Ehrlich carcinoma 5-Fluorouracil chitosan nanoparticles and irradiation treated group.
Apoptotic and necrotic examination in the present study showed that treatment of female mice bearing Ehrlich carcinoma with 5FUCNPs represented low amounts of sporadic late apoptosis in liver hepatocytes and presence of green viable hepatocytes. However, treatment of mice bearing Ehrlich carcinoma with 5FUCNPs and or low doses of γ-irradiation represented high infestations of sporadic necrotic cells in between the hepatic cells and
apoptotic cells infiltrated between the hepatocytes and encircled the portal hepatic vein.
Histopathological Examination of kidney in present study showed normal appearance of kidney when experimental mice-bearing Ehrlich tumor treated with 5-FUCNPs and low doses of γ-irradiation. However, 5-FUCNPs treatment represented disappearance of tumor cells metastasis, bleeding appearance and degenerated glomerulus.
Apoptotic and necrotic examination recorded early and late apoptosis in some of convoluted cell in kidneys of mice-bearing Ehrlich tumor and exposed to low doses of γ-radiation. Late apoptotic state in glomerulus and convoluted tubules cells was shown in mice-bearing Ehrlich tumor and treated by 5FUCNPs or treated by 5-FUCNPs and exposed to low doses of γ-radiation.
Histopathological Examination of spleen tissue in mice bearing EC represented many megakaryocytes in its white pulp. Treatment of mice bearing EC with 5-FUCNPs represented small infraction in peripheral zone , apoptotic cells and megakaryocytes cells in marginal zone and red pulp of the spleen tissue section . Spleen tissue section of mice bearing EC and exposed to γ-radiation
predict splenic faintly stained nodule of white pulp. Its red pulp represented increase extramedullary hematopoiesis, erythyroid and myeloid precursors and large number of megakaryocytes. On the other hand , exposure of female mice bearing EC treated by 5FUCNPs to γ-radiation represented normal appearance of white pulp , giant megakaryocytes in the marginal zone and in the red pulp.
Apoptotic and necrotic examination of spleen tissue of female mice bearing EC treated with 5FUCNPs showed necrotic regions in the red pulp. However, exposure of female mice bearing EC to γ-radiation represented the normal appearance of vital spleen tissue region layers. On the other hand, the combined treatments of mice bearing EC with 5FUCNPs and γ-radiation showed empty regions in the white pulp and some underwent apoptotic cells in red pulp.