ABSTRACT
<p><b>OBJECTIVE</b>To investigate the inhibitory effect of Oridonin injection on heterotransplanted tumors of human gastric adenocarcinoma cell line BGC823 cells in nude mice and explore its mechanism.</p><p><b>METHODS</b>Heterotransplanted models of human gastric adenocarcinoma cell line BGC823 cells in nude mice were established. They were divided at random into three groups as control group, low-dose group and high-dose group. The Oridonin solution at concentration of 37.5 mg x kg(-1 x d(-1) and 75 mg x kg(-1) x d(-1) were injected to the mice in low-dose group and high-dose group, respectively, and 0.9% sodium chloride was injected to the mice of control group per day for 10 days sequentially. The mice of the three groups were sacrificed at 11th day after the first injection of Oridonin. The tumor weight of the sacrificed mice was measured. Morphological and ultrastructural examinations of the tumors were carried out by light and electron microscopy. The expression of bcl-2, Bax, Fas and FasL was detected by immunohistochemistry.</p><p><b>RESULTS</b>Oridonin injection showed a suppressive effect on the growth of heterotransplanted tumors in the nude mice. The tumor growth inhibition rates were 48.5% and 70.7% in the low-dose and high-dose groups, respectively. The morphological study demonstrated that tumor cells displayed a typical appearance of apoptosis. The expression of bcl-2 was down-regulated, while Bax, Fas and FasL were up-regulated.</p><p><b>CONCLUSION</b>Oridonin can markedly inhibit the growth of heterotransplanted human gastric adenocarcinoma in nude mice. It was due, at least in part, to the induction of apoptosis in cancer cells.</p>
Subject(s)
Animals , Humans , Mice , Adenocarcinoma , Metabolism , Pathology , Antineoplastic Agents, Phytogenic , Pharmacology , Apoptosis , Cell Line, Tumor , Diterpenes, Kaurane , Pharmacology , Dose-Response Relationship, Drug , Fas Ligand Protein , Metabolism , Injections , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Proto-Oncogene Proteins c-bcl-2 , Metabolism , Random Allocation , Stomach Neoplasms , Metabolism , Pathology , bcl-2-Associated X Protein , Metabolism , fas Receptor , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To assess the optimal regimen and its mechanism of ZD1839 in combination with SN38, the active metabolite of irinotecan (CPT-11), in the colon cancer cell lines HT-29 and LoVo.</p><p><b>METHODS</b>Chou and Talalay method was used to analyze the combination effects of sequencing of ZD1839 and SN38. Western blotting and immunoprecipitation were used to determine the effects of ZD1839 and/or SN38 on their targeted enzymes and downstream markers. Apoptosis was assayed by analyzing histone-associated DNA fragment.</p><p><b>RESULTS</b>Sequential SN38 followed by ZD1839 produced a synergistic effect. In contrast, SN38 following ZD1839 exhibited an antagonist effect. SN38 markedly inhibited topoisomerase I (Topo-I) activity. ZD1839 did not alter epidermal growth factor receptor (EGFR) expression, but resulted in a complete inhibition of EGFR phosphorylation. Sequential ZD1839 followed by SN38 did not show any enhanced inhibition effect on Topo-I activity, phosphorylation of EGFR and one of its downstream markers MAPK. However, simultaneous SN38 plus ZD1839, and sequential SN38 followed by ZD1839 administrations showed modest inhibition effect on EGFR's another downstream marker AKT. The combination schedules also showed prominent influence on cell cycle distribution. ZD1839 maintained SN38-induced DNA damage and apoptosis.</p><p><b>CONCLUSION</b>Sequential SN38 followed by ZD1839 may be a favorable combination schedule.</p>