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Biological reactive intermediates that mediate dacarbazine cytotoxicity.
- Source :
- Cancer Chemotherapy & Pharmacology; Dec2009, Vol. 65 Issue 1, p89-96, 8p, 3 Diagrams, 5 Charts
- Publication Year :
- 2009
-
Abstract
- In the following, the cellular and molecular mechanism of cytotoxicity induced by prodrug dacarbazine toward the isolated rat hepatocytes was studied. Accelerated cytotoxicity screening technique (ACMS) was used to perform this study. Addition of dacarbazine to isolated rat hepatocytes resulted in reactive oxygen species (ROS) formation, and lysosomal membrane leakiness before hepatocyte lysis occurred. Hepatocyte ROS generation was inhibited by desferoxamine (a ferric chelator). Cytotoxicity was prevented by antioxidants or ROS scavengers (mannitol or dimethylsulfoxide), cytochorome P450 inhibitors (phenylimidazole, diphenyliodonium chloride, 4-methylpyrazole, and benzylimidazole). In addition to lysosomal damage, dacarbazine caused hepatocyte protease activation and cell proteolysis. Dacarbazine cytotoxicity is associated with ROS (H<subscript>2</subscript>O<subscript>2</subscript>, O) generation. It is suggested that H<subscript>2</subscript>O<subscript>2</subscript> could cross the lysosomal membrane, react with lysosomal Fe<superscript>2+</superscript> to form hydroxyl radical (Haber-Weiss reaction) which is the major cause of lysosomal membrane leakiness, proteases, and other digestive enzymes' release and finally the cell death. [ABSTRACT FROM AUTHOR]
- Subjects :
- REACTIVE oxygen species
ANTIOXIDANTS
MANNITOL
PROTEOLYSIS
LIVER cells
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 65
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 44217338
- Full Text :
- https://doi.org/10.1007/s00280-009-1007-8