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Abstract
Summary
This study was done to evaluate the antitumor effect of RXM in a rat model of hepatocellular carcinoma induced by NDEA and CCL4. The study was also investigated the effect of NDEA and CCL4 on lipid peroxidation, NO and on antioxidant enzyme total thiols and the effect of RXM on these biochemical markers.
One hundred and seventy (170) male rats were divided into five groups:
Group (A): Forty rats received single i.p. injection of NDEA (200 mg/ kg b.wt). After one week rats received weekly s.c. injections of CCL4 (3 ml/ kg b.wt) for 6 weeks.
Group (B): Forty rats treated as group A and after 11 weeks from the beginning of the experiment RXM (100 mg/kg b.wt) was injected i.p. thrice weekly for 7 weeks
Group (C): Thirty rats received weekly s.c. injection of CCL4 (3 ml/ kg b.wt) for 6 weeks.
Group (D): Thirty rats received i.p. and s.c. injections of normal saline. After 11 weeks from the beginning of the experiment RXM was injected i.p. thrice per week for 7 weeks.
Group (E): Thirty male rats served as control and received i.p. and s.c. injection of normal saline.
Five rats from each group were slaughtered after 8, 9 and 10 week for detection of preneoplastic changes to determine the perfect time for administration of RXM. The rest of animals were slaughtered at the end of the experiment after 32 weeks.
Specimens from liver, lungs, kidneys, heart and spleen were taken after 8, 9 and 10 weeks from the beginning of the experiment and the end of the experiment for histopathological examination. Blood samples were collected for biochemical analysis included assay of lipid peroxidation, determination of nitric oxide and serum total thiols.
Computerized morphometrical analysis of cell size (μm2), nuclear size (μm2) and nuclear/cytoplasmic ratio was done by research microscope upgradeable to professional digital image analysis system.
NDEA and CCL4 induced proliferating and neoplastic lesions in liver and lung. The proliferating and neoplastic lesions of hepatic parenchyma included focal eosinophilic preneoplastic changes (56%), diffuse eosinophilic preneoplastic changes (40%), large cell dysplasia (4%), hepatoma (4%) and hepatocellular carcinoma (24%). Proliferating lesions of bile duct included bile duct hyperplasia (40%), cholangiofibrosis (12%), cystic cholangioma (12%) and cholangiocarcinoma (4%). Proliferation of oval cells (72%), spongiotic pericytoma (24%) and lipoma (4%) were also reported. In lungs, the proliferating and neoplastic lesions were seen in the alveoli and the bronchiole. The lesions included alveolar hyperplasia (36%), bronchiolar hyperplasia (16%), squamous metaplasia (8%), bronchiolo-alveolar adenoma (4%) and bronchiolo-alveolar carcinoma (20%).
In the liver, treatment with RXM resulted in decrease percentage of focal and diffuse eosinophilic preneoplastic changes to 8% and 16%, respectively, bile duct hyperplasia to 16%, oval cell proliferation to 12 % and spongiotic pericytoma to 4%. RXM inhibited the development of large cell dysplasia, hepatoma, hepatocellular carcinoma, cholangiofibrosis, cystic cholangioma, cholangiocarcinoma and lipoma.
In lungs, treatment with RXM inhibited the development of alveolar hyperplasia, squamous metaplasia, bronchiolo-alveolar adenoma and bronchiolo-alveolar carcinoma and decreased the percentage of bronchiolar hyperplasia to 4%.
No proliferating lesions in liver and lung were observed in CCL4 group, RXM group or Control group.
The computerized morphometric analysis revealed that there was extremely significant increase in cell size and nuclear size of eosinophilic preneoplastic foci, diffuse preneoplastic change and large cell dysplasia when compared with the control liver.
There was an extremely significant increase in nuclear/cytoplasmic ratio and decrease in cell size of poorly differentiated hepatocellular carcinoma and well differentiated HCC when compared with the control liver. There was extremely significant decrease in nuclear size of poorly differentiated HCC when compared with control liver. No significance difference was observed in nuclear size of well differentiated hepatocellular carcinoma when compared with control liver. In conclusion, all the morphometric data showed pronounced differences between preneoplastic changes, benign and malignant lesions in liver.
The biochemical results showed that there was an extremely significant decrease in serum lipid peroxides in NDEA+CCL4 group, increase in the serum nitric oxide of NDEA+CCL4 group and extremely significant decrease in the serum total thiols in NDEA+CCL4 group when compared with the serum of control group. No significance difference was observed in lipid peroxides, nitric oxide and total thiols in NDEA+CCL4+RXM group, CCL4 group and RXM group when compared with the serum of control group.
It has been concluded that rats received NDEA and CCL4 exhibited a wide varieties of proliferating and neoplastic lesions in liver and lung. Such lesions varied from those representing development of neoplastic potentiality to those representing preneoplastic changes (focal and diffuse), hyperplasia, metaplasia and dysplasia, then up to those representing a cancer formation of benign and malignant type.
The use of RXM as anticarcinogenic agent inhibited the development of both preneoplastic changes in nearly 76 % of rats and neoplastic changes in nearly 100% of rats during NDEA and CCL4 induced hepatocarcinogenesis and pulmonary carcinogesis. Moreover, serobiochemical studies reported that RXM modulated the level of lipid Peroxide, nitric oxide and total thiols to nearly normal level and reversing the oxidant- antioxidant imbalance to which the inhibitory action of tumor proliferation was attributed.