Cisplatin, doxorubicin and fluorouracil (5-FU), drugs belonging to different chemical classes, have been extensively used for chemotherapy of various cancers. Despite extensive investigations into their hepatotoxicity, there is very limited information on their effects on the structure and ultra-structure of liver cells in vivo. Here, we demonstrate for the first time, the effects of these three anticancer drugs on rat liver toxicity using both light and electron microscopy. Light microscopic observations revealed that higher doses of cisplatin and doxorubicin caused massive hepatotoxicity compared to 5-FU treatment, including dissolution of hepatic cords, focal inflammation and necrotic tissues. Interestingly, low doses also exhibited abnormal changes, including periportal fibrosis, degeneration of hepatic cords and increased apoptosis. These changes were confirmed at ultrastructural level, including vesiculated rough endoplasmic reticulum and atrophied mitochondria with ill-differentiated cisternae, dense collection of macrophages and lymphocytes as well as fibrocytes with collagenous fibrils manifesting early sign of fibrosis, especially in response to cisplatin and doxorubicin -treatment. Our results provide in vivo evidence, at ultrastructural level, of direct hepatotoxicity caused by cisplatin, doxorubicin and 5-FU at both light and electron microscopi. These results can guide the design of appropriate treatment regimen to reduce the hepatotoxic effects of these anticancer drugs.

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Chemoprevention by dietary constituents holds great promise to control cancer. Grape seeds(GSE) and skin (GSK) contain large amounts of phytochemicals such as flavonoids, phenolic acids, and anthocyanidins, which play an important role as chemopreventive and anticancer agents. This study was undertaken to investigate the chemopreventive effects of GSE and GSK efficacies and associated mechanisms on tumor growth in mice. GSE & GSK were separated from the pulp of grape Vitis vinifera, dried and ground to powder. Equal amounts of GSE & GSK were mixed uniformly with the standard diet powder at concentrations of 10% (w/w). The supplemented diet was started two weeks before tumor cells inoculation and continued until the end of the experiment. Female Swiss albino mice were inoculated subcutaneously with 2.5x106 Ehrlich ascites carcinoma (EAC) cells. Tumor growth was monitored for 30 days.Cell cycle progression was measured and the apoptotic effect of GSE and GSK on tumor cells were evaluated by flow cytometric analysis, histopathology and transmission electron microscopy examination. GSE & GSK intake prevented tumor development in 47% of the animals. Tumor volume and tumor weight measured at the termination of the experiment were reduced by 93.9 %& 86.3 %, p< 0.001) respectively as compared to the untreated tumor- bearing mice. GSE& GSK induced a marked increase in the percentage of apoptotic tumor cells as determined by flow cytometric analysis and confirmed by histopathological and electron microscopy examination. These changes were associated with significant G1-phase cell cycle arrest, decrease in the expression of Bcl-2, increase of the expression of p53 and induced caspase-3 activation in the tumor cells. Our data demonstrated that grape seeds& skin intake resulted in profound cell growth inhibition by a mechanism involved G1-phase cell cycle arrest, and apoptosis. Therefore, dietary grape seeds and grape skin possess cancer chemopreventive potential and provide support for their use in human cancer chemoprevention. Citation Format: Nariman K. Badr El-Din, Doaa A. Ali, Rania F. Abou-El-Magd, Nahed A. Soliman. Cancer chemopreventive potential of grape seeds and skin in mice inoculated with Ehrlich ascites carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4862. doi:10.1158/1538-7445.AM2013-4862