Comparison of efficacy and toxicity profile between intraperitoneal and intravenous topotecan in human ovarian cancer xenografts.
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OBJECTIVE: To compare the therapeutic and toxic profile of topotecan given intraperitoneally with intravenously in human ovarian cancer xenografted into athymic nude mice. METHOD: Eighty female Balb-c/nu-nu mice were randomized assigned into eight groups (n=10). Xenografts resulted from intramesentery injection of cultured human ovarian cancer cells SKOV3 in athymic mice. Onset of intraperitoneal treatment with either topotecan or cisplatin (7.5 mg/kg) was on day 7. Animals scheduled for topotecan i.p. received intraperitoneal application of topotecan (1.5 mg/kg x 2, 3.0 mg/kg x 2, 6.0 mg/kg x 2 or 10.0 mg/kg x 1). Animals scheduled for topotecan i.v. received intravenous administration of topotecan (6.0 mg/kg x 2 or 10.0 mg/kg x 1). Two weeks after drug application animals were killed. Tumor growth inhibition were assessed and compared with untreated mice and cisplatin intraperitoneally administered mice. Acute toxicity was determined by loss of body weight. Cell cycle division and apoptosis after drug administration was determined by flow cytometric analysis. RESULTS: In a panel of ten tumour xenografts, intraperitoneal topotecan was significantly more effective than intravenous administration. The toxicity profile suggested a better tolerability in terms of weight loss after intraperitoneal administration than cisplatin control. Topotecan 10.0 mg/kg i.p. per day (1 day) schedule was an optimal treatment for ovarian cancer and well tolerated by mice with no signs of acute toxicity. Topotecan and cisplatin induce cells G0-G1 arrest and apparent apoptosis. No significant difference among mice treated with topotecan intraperitoneally or intravenously or cisplatin was observed in term of apoptosis and cell cycle perturbation. CONCLUSION: The results may have implications for the future design of clinical studies on intraperitoneal application of topotecan. It suggests that apoptosis and cell cycle perturbation play an limited role in the mechanism of topotecan administration. (+info)
Cigarette smoke extract inhibits the proliferation of alveolar epithelial cells and induces apoptosis.
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Cigarette smoke extract (CSE) contains abundant oxidants and free radicals. Oxidative stress caused by cigarette smoking results in the destruction of the alveolar cell walls and emphysema. However, there exists discrepancy about how CSE works in the process. In the present study, we observed the effect of CSE on the cell growth of type II alveolar epithelial cell-derived A549 cell line, and provided molecular understanding of this effect. The MTT assay results showed that CSE decreased the cell viability of A549 cells in a dose- and time-dependent manner, and cell cycle was arrested in G(1)/S phase. Furthermore, CSE-induced apoptosis of A549 cells was verified by Hoechst 33258 staining, electron microscopy in morphology, and the appearance of DNA fragmentation and annexin V-FITC/propidium iodide (PI) staining assay at molecular level. It was found that CSE treatment resulted in the upregulation of Fas/APO-1 receptor and activation of caspase-3. CSE also initiated accumulation of intracellular reactive oxygen species, which was detected by laser confocal microscopy. Taken together, CSE could inhibit the cell growth and induce apoptosis of A549 cells through Fas receptor pathway. Oxidative stress caused by CSE may be the radical factor leading to apoptosis as well as cell growth inhibition in alveolar epithelial cells. (+info)
Glycogen synthase kinase 3beta induces cell cycle arrest in a cyclin D1-dependent manner in human lung adenocarcinoma cell line A549.
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The effect of glycogen synthase kinase 3beta (GSK3beta) has been repeatedly implicated in cell proliferation, but studies on the effect of GSK3beta in different cell lines with different stimuli have drawn different conclusions. To investigate the direct effect of GSK3beta on cell growth in human lung adenocarcinoma cell line A549, we changed its activity by transient transfection with two kinds of GSK3beta mutant plasmids, constitutively active form S9A-GSK3beta and dominant negative form KM-GSK3beta. Twenty-four hours later, cell counting, flow cytometry and Western blot detection were made respectively. The results showed that enhancing GSK3beta activity caused a decrease in cell number, as well as a higher percentage of cells at G(1) phase. Further, the expression of cyclin D1 was down-regulated by GSK3beta. Taken together, our observations suggest that GSK3beta may induce G(1) cell cycle arrest in a cyclin D1-dependent fashion and therefore possibly plays a growth-inhibitory role in A549 cells. (+info)
Adenine nucleotide translocase 4 deficiency leads to early meiotic arrest of murine male germ cells.
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