ABSTRACT
Hepatic stellate cells (HSC) play an important role in the development of liver cirrhosis. They are a major source of extracellular matrix and during fibrogenesis undergo an activation process characterized by increased proliferation and collagen synthesis. In this study, we investigated the anti-fibrogenic effect of zinc supplementation on zinc deficiency induced HSC activation. Isolated HSC were incubated with or without zinc chelator, diethylenetriamine penta-acetic acid (DTPA). Type I collagen expression in HSC was detected by immunohistochemistry. The involvement of glutathione (GSH) homeostasis in the anti-fibrogenic action of zinc was also investigated, as GSH is implicated in many cellular events, such as regulation of cell proliferation, remodeling of extracellular matrix and oxidative stress. Intracellular GSH was measured by HPLC. Enhanced type I collagen expression, apoptosis and cell cycle arrest were found in HSC when DTPA was added, but they were inhibited with supplementation with zinc. Zinc deficiency caused a reduction in intracellular GSH 8 h after the addition of DTPA compared with control levels. The results of this study show that in HSC, the chelation of zinc triggers a progression of collagen synthesis and this involves the depletion of intracellular GSH levels after the addition of DTPA.
Subject(s)
Glutathione/physiology , Liver/metabolism , Zinc/metabolism , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cells, Cultured , Collagen Type I/biosynthesis , Glutathione/analysis , Immunoenzyme Techniques , Liver/drug effects , Liver/pathology , Male , Polyamines/pharmacology , Rats , Rats, Wistar , Zinc/deficiencyABSTRACT
Advanced cervical cancer has been predominantly treated with a combination of external beam and brachytherapy in Japan. Recent studies suggest concurrent use of cisplatin and radiation treatment has superior disease control to radiation only treatment. We have conducted a phase I pilot study of concurrent use of weekly nedaplatin (30 mg/m2) and sequential external beam and brachytherapy in advanced stage or recurrent uterine cervical cancer patients (n = 6). All patients completed the treatment without serious complications. Five patients had complete responses and one a partial response. The average AUC of nedaplatin after one administration was 5.0 micrograms/ml.hr. The therapeutic index was 2. We concluded that concurrent use of weekly nedaplatin and radiation is well tolerated by Japanese women, and may well be an excellent therapeutic modality for selected cases of advanced or recurrent cervical cancer.
