الفهرس 
Chapter I (Review of literature)Only 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of death and the fifth most common malignancy worldwide. Conventional treatments of HCC as radiotherapy and chemotherapy have many disadvantages such as various side effects on normal cell, low success rate, high risk of recurrence and high degree of mortality. In addition, tumors often acquire resistance against chemotherapeutics. Consequently, the development of new safe and effective treatments is extremely needed. One of these alternative approaches is the using of anticancer peptides derived from animal venoms including snakes. Despite its toxic effect, snake venom has the ability to target cellular metabolism alterations with a major effect on the tumor cells when compared with the normal cells. It can induce the blockage of some specific ion channels, inhibiting angiogenesis, suppressing metastasis and activating the intracellular pathways causing apoptosis in tumor cells rendering it a potential anti-oxidizing and anticancer complex. In the present study, we assess the potency of crude venoms isolated from the Egyptian snakes Naja nubiae and Cerastes cerastes, which are considered to be two of the most prevalent venomous snakes in Egypt, as anti-HCC in rat models. Initially, the venom was extracted from about 10 adult specimens of Naja nubiae snakes and 8 adult specimens of Cerastes cerastes viper snakes and the median lethal doses (LD50) of both venoms were determined. The chemically HCC-induced model was developed in albino rats using diethyl nitrosamine (DENA)/carbon tetra chloride (CCl4). Briefly, Eighty four adult male albino rats were equally divided into seven groups, group 1: served as a negative control group, included rats given only the vehicle (single i.p. injection of sterile 0.9% saline, two weeks later, i.p. injections of olive oil at a dose of 3ml/kg/week were administrated for 6 weeks, followed by saline i.p. injections twice a week for 21 days, group2: Naja nubiae venom-treated group, included rats that received the vehicle, followed by i.p. injections of 0.1 LD50 of soluble Naja nubiae venom (in 0.9% saline) twice a week for 21 days, group 3: Cerastes cerastes venom-treated group, included rats that received the vehicle, followed by i.p. injections of 0.1 LD50 of soluble Cerastes cerastes venom (in 0.9% saline) twice a week for 21 days. Groups 4-7 received a single i.p. injection of DENA at a dose of 200 mg/kg, two weeks later, they received i.p. injections of CCl4 (3 ml/kg/week as 1:1 dilution in olive oil), for 6 weeks to promote the carcinogenic effect of DENA, group 4: HCC group received only saline and acted as a positive control, group 5: HCC- Naja nubiae venom treated group, received 0.1 LD50 N. nubiae venom twice a week, i.p., for 21 days, group 6: HCC- Cerastes cerastes venom treated group, received 0.1 LD50 C. cerastes venom twice a week, i.p., for 21 days, group 7: HCC- cisplatin venom treated group, received cisplatin at a dose of 1.5 mg/kg twice a week, i.p., for 21 days. At the end of the experiment the animals were weighted individually to determine the final body weight, then they was sacrificed and the liver samples from both untreated and venom-treated groups were removed, weighed, and assessed by biochemical, molecular, histopathological and immunohistochemical techniques. The results showed that the two venoms induced anticancer effect as evidenced by significant improvement in the final body weight, significant decrease in the liver weight and the relative liver weight. Also liver and kidney functions and the antioxidant status were improved as indicated by significant decrease in the serum ALT, AST, creatinine, urea, MDA and NO levels, with significant improvement in the serum total protein, albumin and the antioxidant enzymes SOD and GPx levels compared with the HCC untreated animals. At the molecular level, both venoms induced apoptosis which were mediated by up regulation of pro-apoptotic genes Bax, Caspase 3, FAS and TRAIL and down regulation of anti-apoptotic gene Bcl-2 in the HCC-venom treated animals without any effect on the normal animals. Moreover, the histopathological examinations of liver tissues also showed marked improvement in the venoms-treated groups compared with HCC, untreated, group. Using immunohistochemical techniques, the expression of PCNA and Ku70 were determined. Interestingly, treatment with 0.1 LD50 of Naja nubiae venom and 0.1 LD50 of Cerastes cerastes venom decreased the expression of Ku70 and PCNA in liver tissues of the HCC-venom treated animals without any effect on the normal animals which received the venom. Our results indicate that Naja nubiae venom and Cerastes cerastes venom may serve as a novel potential therapeutic pro-drug against HCC.