الفهرس 
Introduction And Aim Of The WorkOnly 14 pages are availabe for public view
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Abstract
The present study aimed to investigated a new systemic drugs regimen based on selective tumour vascular disruption using CA4-P and vincristine in the treatment of HCC in rats by individual administration. In addition to, evaluated the synergistic effect which could be achieved by combined administration of both drugs and determine the possible underlying mechanisms both in vivo and in vitro. Furthermore, this study evaluated the anticancer activity of newly designed CA4-P analogue against HCC and compare its activity to the parent compound (CA4-P).
In vitro study used HepG2 cell lines to evaluate the cytotoxic (antitumour) activity, tubulin protein inhibition and cell cycle analysis of the investigated drugs. While, in vivo study used DENA + CCl4 model to induce HCC in rats.
The following parameters were determined: hepatic relative weight, number of hepatic nodules, relative volume of hepatic nodules, hepatic tissue content of tubulin, histopathological examination of the hepatic tissue, hepatic tissue lipid peroxidation, hepatic tissue carbonyl content, serum ALT, serum AST, hepatic tissue TNF-α and hepatic AFP concentrations.
CA4-P showed a potent anticancer activity against HCC both in vitro and in vivo; in vitro by a dramatically decrease in the viability of the treated HepG2 cell lines, in vivo as observed in the significant decrease in the number of hepatic nodules, hepatic relative weight compare to non-treated animals and decreased level of AFP as a biochemical marker on the degree of HCC.
New mechanisms were found by which CA4-P can conduct its anticancer activity against HCC including, tubulin protein inhibition both in vitro and in vivo, oxidative stress generation resulting in an increased hepatic MDA and protein carbonyl levels and increased TNF-α production inside hepatic tissue leading to hepatic tumor cells ischemia and necrosis as shown in the hepatic histopathological examination.
Newly synthesized CA4-P analogue has a good anticancer activity against HCC. In addition, CA4-P analogue showed a superior activity against HCC than its parent compound (CA4-P) with about twofold tubulin inhibitory effect more than CA4-P, with increased ROS generation and TNF-α production. Indicting on the similarity in the mechanism of action between CA4-P analogue and CA4-P, with moderate superior activity for CA4-P analogue.
The effect of vincristine on HCC revealed a potent in vitro anticancer effect against HCC cell line as it was seen in cells cytotoxicity test and tubulin inhibitory effect which was more potent than CA4-P, while in vivo study showed a moderate activity against induced HCC in rats which was less potent than CA4-P.
A strong synergistic anticancer effect in vitro was clearly observed by CA4-P and vincristine co-application, as shown in cell cytotoxicity test. Moreover, in vivo combined administration of these compounds clearly displayed an enhanced anticancer activity against HCC, as both number of heptic nodules and hepatic relative weight were significantly decreased compare to other treated groups by either CA4-P or vincristine individually administration. Moreover, ROS generation, TNF- production and tubulin inhibition were greatly enhanced by this combination.