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Proline analogue of nitrosourea as a new cytotoxic prodrug

Anna Stankiewicz-Kranc 1Anna Bielawska 2Krzysztof Bielawski 2Elżbieta Skrzydlewska 1

1. Department of Analytical Chemistry, Medical University of Białystok, Białystok 15-089, Poland
2. Department of Medical Chemistry and Drug Technology, Medical University of Białystok, Białystok 15-089, Poland

Abstract

Carmustine (bis-chloroethyl-nitrosourea) is anticancer compound in the nitrosourea class commonly used in the treatment of malignant gliomas, multiple myeloma and breast cancer. Carmustine undergoes hydrolysis in vivo to form reactive metabolites which cause alkylation of biologic molecules and cross-linking of DNA. High toxicity and low selectivity of carmustine reduces its safe use in the cancer therapy. Therefore, there is need for new compounds characterized by similar therapeutic activities but less harmful sides effects. As a result, proline analogues of nitrosourea have been synthesized. It has substituted one chloroethyl group by proline and reveals higher selectivity than carmustine. Our aim was to compare the influence of carmustine and new proline analogue of nitrosourea (N-[N’-(2-chloroethylo)-N’-nitrosocarbamoyl]-proline) (AB) on the antioxidative system of fibroblasts and cancer cells MOLT4, to examine redox potential mechanisms of this proline analogue. Administration of carmustine and AB compound caused decrease in activities of antioxidative enzymes in fibrobasts as well as in MOLT4 and these changes were accompanied by increase in hydrogen peroxide level as well as lipid peroxidation marker - MDA. Moreover, administration of carmustine caused increase in fibroblasts glutathione concentration. Increase in dityrosine-marker of protein oxidative modification in fibroblasts and MOLT4 was also observed after administration of both compounds. Finally, it may be concluded that, new proline analogue of nitrosourea causes number of changes in antioxidative system of cancer cells probably by increase in generation of hydrogen peroxide. It was confirmed by enhancing the process of oxidative modification of proteins and lipids. Lack of significant differences in fibroblasts and MOLT4 antioxidative system reaction of examined compounds result from the similarly activity of prolidase – hydrolase which cut off proline residue.

 

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Related papers

Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Anna Stankiewicz-Kranc
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-03-14 12:54
Revised:   2009-06-07 00:48