eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
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vol. 2

Original paper
Modulation of the tissue defense system by squalene in cyclophosphamide induced toxicity in rats

Subramanian Senthilkumar
Kesavarao Kumar Ebenezar
Venkatachalem Sathish
Surinderkumar Yogeeta
Thiruvengadam Devaki

Arch Med Sci 2006; 2, 2: 94-100
Online publish date: 2006/06/22
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A free radical is any atom or molecule, capable of independent existence that has one or more unpaired electrons. If uncontrolled by the protective mechanisms, it leads to a pathological effect which causes damage to cellular membranes, proteins and nucleic acids [1]. The major limitation of cancer chemotherapy is the injury of the normal tissue, leading to multiple organ toxicity [2, 3]. CP is an alkylating agent, the most commonly used anticancer and immunosuppressant drug. It is used for the treatment of chronic and acute leukemias, multiple myeloma, lymphomas, and rheumatic arthritis and also in the preparation for bone marrow transplantation [4, 5]. High-dose chemotherapy administered in bone marrow transplantation regimens commonly induces nausea, emesis, oropharyngeal inflammation, abdominal pain and diarrhea [6]. Phosphoramide mustard and acrolein are the two active metabolites of CP formed by hepatic microsomal cytochrome P450 mixed functional oxidase system [7]. CP’s antineoplastic effects are associated with the phosphoramide mustard, while the acrolein is linked with its toxic side effects [8]. Chemotherapy and radiation therapy are associated with increased formation of reactive oxygen species (ROS) and depletion of critical plasma and tissue antioxidants [9]. Two reactive moieties of acrolein, an aldehyde group and an unsaturated bond, have the potential to cross-link to nucleophilic groups on two different proteins [10]. Acrolein is a relatively long-lived molecule that might diffuse some distance before reacting with proteins [11]. Acrolein interferes with the tissue antioxidant defense system [12], produces highly reactive oxygen free radicals [13] and is mutagenic to mammalian cells [14]. Due to the highly reactive nature, free radicals can readily combine with other molecules, such as enzymes, receptors, and ion pumps, causing oxidation directly, and inactivating or inhibiting their normal functions [15]. Liver disorders were observed in the elevated therapeutic dose of CP [16-19]. The nephrotoxicity of CP was evidenced by the proximal tubular damage, a significant reversible depolarization and a decrease in conductance [20, 21]. CP induced urinary bladder inflammation has demonstrated alterations in neurochemical [22] electrophysiological properties [23] of the bladder. Effects due to CP toxic metabolites could be avoided by detoxifying with agents which are able to conjugate or quench these toxic...

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enzymic antioxidants, TBARS, reactive oxygen species, free radicals, liver, kidney

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