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Speciation and Reactivity of the Antineoplastic Copper-Based Compound: Casiopeina II.

Rivero-Muller, Adolfo. (1999) Speciation and Reactivity of the Antineoplastic Copper-Based Compound: Casiopeina II. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Casiopeinas are a family of copper complexes developed for a range of biological activities. Casiopeina II {[Cu(4,7-dimethyl-1,10-phenanthroline)(glycine)]NO3}, typical of this family, has shown promising anticancer activity in vitro and in vivo although it causes some haemolytic anaemia. The exact mechanism of this toxicity is unknown but may be ascribed to the known toxicity of free Cu2+. In this work casiopeina II (3H-4,7-dm-phenanthroline-labelled) was iv injected into Wistar/Albino male rats (±250 g) at a dose of 2.5 mg/Kg to determine the fate of the complex and its stability in vivo. The copper centre and the 3H-4,7-dm-phenanthroline (3H) moieties were followed at various time points after the intravenous administration. The speciation of the complex in vivo and in vitro, showed that casiopeina II binds with plasma proteins (albumin) but rapidly enters the red blood cells and is transported to all the major tissues. The 3H label was not retained in any tissues except liver while copper was mainly retained in the tissues. In bile copper excretion was more rapid than the 3H label. While significant amounts of 3H were excreted in urine there was no elimination of copper via this route. The differences in distribution and excretion of the copper and 3H ligand moieties indicate rapid in vivo dissociation of casiopeina II. This dissociation may be enhanced by the metabolism of the ligand. The retention of copper in the tissues, particularly in the liver, resulted in an increase of copper-binding proteins (caeruloplasmin and metallothionein). During the first few hours after the administration of casiopeina II there was a depletion of superoxide dismutase (SOD) in red blood cells (RBC) and an increase of lipid peroxidation products in plasma. This corresponds with the reported haemolysis. Administration of casiopeina II to Ginea pigs (same route and dose as in the rat), which exhibit a lipoprotein profile similar to humans, lead to oxidation of the low density lipoproteins (LDL) in plasma. Casiopeina produces apoptosis in L1210 (murine leukaemia) and COS1 (green monkey kidney) cells in vitro. In the latter, casiopeina II was found to lead to the release of cytochrome c from the intermembrane space of mitochondria. This is a known intracellular initiator of the apoptotic pathway. Interestingly it was not detected in L1210 cells suggesting a different apoptotic pathway. Consistent with this when isolated mitochondria were exposed to casiopeina II, pore transition was induced leading to release of matrix contents. Casiopeina II binds tightly to isolated and nuclear DNA and isolated RNA, and in the presence of ascorbate (AsA) and molecular oxygen it degrades the genetic material. This "nuclease" activity was found to be related to reactive oxygen species (ROS) generation in close proximity to the genetic material. Interestingly, EDTA and trientine inhibited this reaction. Its activity as an antiviral agent tested with a feline calcinovirus (RNA virus) in vitro indicated a potential for viral inhibition. Casiopeina II was highly toxic to cells in culture but addition of catalase and/or SOD protected against this cytotoxicity. Neither copper or phenanthroline alone showed any of the above effects leading to the conclusion that the complex (at least the Cu-phen component) is necessary for its antineoplastic effect and also for its toxicity. The toxicity and biological activity of casiopeina II may be a consequence of its exact structure and composition. Stabilising the casiopeina complex may alter its antineoplastic activity as well as reduce its toxicity.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Rivero-Muller, Adolfo.
Date : 1999
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1999.
Depositing User : EPrints Services
Date Deposited : 06 May 2020 14:37
Last Modified : 06 May 2020 14:42
URI: http://epubs.surrey.ac.uk/id/eprint/856270

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