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Iron binding by certain anticancer pharmaceuticals

McLay, Paula (1992) Iron binding by certain anticancer pharmaceuticals. PhD thesis, Murdoch University.

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The importance of Fe(III)-chelation in the biological activity of the anticancer pharmaceutical Razoxane has been investigated. Since Razoxane is known to be hydrolysed in vivo to form a potential complexing agent, the observed biological effect o(Razoxane (ICRF 159) and two less active homologues (ICRF 154 and ICRF 192) were compared with the properties of their hydrolysis products; ICRF 198 (N ,N'-dicarboxamidomethy 1-N ,N'-dicarboxymethyl-1,2-diaminopropane, ICRF 175 (N,N'-dicarboxamidomethyl-N,N'-dicarboxymethyl-1,2-diamino-ethane) and ICRF 226 (N,N'-dicarboxarnidomethyl-N,N'-dicarboxymethyl-1,2-diaminobutane), respectively. The equilibrium constants for the binding of these compounds with Fe(III) were determined by cyclic voltammetry and potentiometric titration. In addition, equilibrium constants of ICRF 175 and 198 binding with Zn(II) and of citrate binding with Fe(III) were determined. Relevant equilibrium constants for the binding of the proton with these complexing agents were also obtained. These constants were incorporated into a computer simulation model of blood plasma, permitting calculation of the extent of chelation of these agents in vivo. Differences were observed in the ability of the compounds to complex Fe(III) under physiological conditions. Nevertheless, it was concluded that the anticancer activity of Razoxane is not directly related to Fe(III) chelation.

The rates of reaction of superoxide (O-2) with the Zn(II), Cu(II) and Fe(III) complexes of EDTA, DTPA, ICRF 175, I 98 and 226 were subsequently measured by pulse radiolysis. Significantly, ICRF 198-Fe(III) was found to react relatively rapidly with superoxide. In addition, the computer simulations indicate that the presence of ICRF 198 would restrict the formation of iron complexes of the anticancer pharmaceutical Adriamycin, these complexes being implicated in its cardiotoxicity. The ability to compete in vivo for iron and to react with superoxide thus appear to be important aspects of the mechanism of action of Razoxane to protect against the clinically-important side-effects of Adriamycin administration.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Mathematical and Physical Sciences
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): May, Peter and Hefter, Glenn
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