Satraplatin activation by haemoglobin, cytochrome C and liver microsomes in vitro.
BACKGROUND
Satraplatin is thought to require reduction to a reactive Pt(II) complex (JM118) before exerting chemotherapeutic activity. In this study, we investigated the role of heme proteins in this reductive activation of satraplatin.


METHODS
Satraplatin was incubated in solution with heme proteins and liver microsomes. The oxidation state of heme iron was monitored by visible absorption spectrometry. Satraplatin and JM118 were detected using a sensitive and specific HPLC-ICPMS assay.


RESULTS
Satraplatin was stable in solutions containing haemoglobin, cytochrome c, glutathione, liver microsomes or NADH alone. However, in solutions containing haemoglobin plus NADH, satraplatin disappeared with a half-life of 35.8 mins. Under these conditions, satraplatin was reduced to JM118 and haemoglobin was oxidised to methaemoglobin. The reaction between haemoglobin and satraplatin was inhibited by carbon monoxide or by cooling the reaction solution. Cytochrome c and liver microsomes also reduced satraplatin to JM118 in a manner that depended upon the presence of NADH and was inhibited by carbon monoxide.


CONCLUSIONS
This study has identified a mechanism of satraplatin activation involving metal-containing redox proteins and the transfer of electrons to the Pt(IV) drug from protein-complexed metal ions. Heme proteins may act by this mechanism as reducing agents for the activation of satraplatin in vivo.
Carr
Jocelyn L
JL
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Tingle
Malcolm D
MD
McKeage
Mark J
MJ
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D045304:Cytochromes c / Q000378:metabolism*; D004579:Electron Transport; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006420:Hemeproteins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction
D000970:Antineoplastic Agents; D006420:Hemeproteins; D006454:Hemoglobins; D009944:Organoplatinum Compounds; C097758:amminedichloro(cyclohexylamine)platinum(II); D009243:NAD; C081294:satraplatin; D045304:Cytochromes c; D005978:Glutathione