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Cancer Chemotherapy and Pharmacology

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01-12-2009 | Original Article

Biological reactive intermediates that mediate dacarbazine cytotoxicity

Authors: Jalal Pourahmad, Marzieh Amirmostofian, Farzad Kobarfard, Jafar Shahraki

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2009

Abstract

Purpose

In the following, the cellular and molecular mechanism of cytotoxicity induced by prodrug dacarbazine toward the isolated rat hepatocytes was studied.

Method

Accelerated cytotoxicity screening technique (ACMS) was used to perform this study.

Result

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.

Conclusion

Dacarbazine cytotoxicity is associated with ROS (H₂O₂, O ₂ ^•− ) generation. It is suggested that H₂O₂ could cross the lysosomal membrane, react with lysosomal Fe²⁺ 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.

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Title: Biological reactive intermediates that mediate dacarbazine cytotoxicity
Authors: Jalal Pourahmad
Marzieh Amirmostofian
Farzad Kobarfard
Jafar Shahraki
Publication date: 01-12-2009
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1007-8

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Abstract

Purpose

Method

Result

Conclusion

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