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Book of Abstracts - Ruhr-Universität Bochum

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P-02<br />

ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />

Degradation <strong>of</strong> Platinum-Based Anticancer Drugs by Thiosulfate Ions:<br />

an EXAFS Study<br />

Diane Bouvet- Muller, a A. Michalowicz, a S.Crauste-Manciet, b,c and K. Provost a<br />

a Institut de Chimie et des Matériaux Paris Est, ICMPE/SAX, UMR 7182 CNRS-Paris Est, 2 à 8 rue<br />

Henri Dunant, 94320 Thiais, France, b Laboratoire de Pharmacie Galénique, Université Paris V,<br />

75006 Paris, France, c Service de Pharmacie, CHI Poissy Saint Germain en Laye, 78105 Saint<br />

Germain en Laye, France. E-mail: muller@u-pec.fr<br />

Three platinum complexes are currently used worldwide: cisplatin, carboplatin and oxaliplatin. 1<br />

Cisplatin is the most common, and its reactivity has been widely studied. On the contrary, derivatives<br />

<strong>of</strong> carboplatin and oxaliplatin deserve to be structurally characterized in order to understand their<br />

mode <strong>of</strong> action and stability in solution. This study takes place in the work carried out by our group on<br />

the behavior <strong>of</strong> these platinum complexes in presence <strong>of</strong> various halogen and sulfur ligands. 2-4<br />

These drugs react rapidly with nucleophilic species in solution. Their degradation has two<br />

consequences: in vitro, it can compromise the stability <strong>of</strong> the drug in solution before administration; in<br />

vivo, the structural modification <strong>of</strong> these molecules can induce notable changes in their modes <strong>of</strong><br />

action. Sulfur nucleophilic ligands are particularly interesting: 5 they play a major role in the<br />

detoxification <strong>of</strong> the drugs. Particularly, thiosulfate ions are used to prevent nephro- and ototoxicity. 6<br />

This study deals with the reaction <strong>of</strong> carboplatin and oxaliplatin with thiosulfate. For both drugs, the<br />

reaction products remain in solution. Thus we used X-ray absorption spectroscopy in order to<br />

characterize their structures. Spectra have been recorded for different reaction times (from one hour to<br />

one month) and for different drug/thiosulfate ratios (from 1/2 to 1/40). For a 1/2 ratio at one month <strong>of</strong><br />

reaction, we observe the displacement <strong>of</strong> the carboxylate ligand for both drugs,and a strong similarity<br />

<strong>of</strong> the signal between 3 and 4 Å. This EXAFS signal can be used as a signature <strong>of</strong> the Pt-Thiosulfate<br />

binding, in order to model the complete reaction products structures in solution.<br />

On this basis, the spectral and structural evolution as a function <strong>of</strong> the reaction time on one hand and<br />

<strong>of</strong> the drug/thiosulfate ratio on the other hand are discussed.<br />

References<br />

1. L.R. Kelland, Nat. Rev. Cancer 2007, 7, 573-584.<br />

2. D.Bouvet, A. Michalowicz, S. Crauste-Manciet, D. Brossard, K. Provost. Inorg. Chem 2006,<br />

45, 3393-3398.<br />

3. D. Bouvet et al. J. Synchr. Rad. 2006, 13, 477-483.<br />

4. K. Provost et al. Biochimie 2009, 91, 1301-1306.<br />

5. J. Reedjik, Chem. Rev. 1999, 99, 2499-2510.<br />

6. D.J. Leitao, B.W. Blakley. Journal <strong>of</strong> Otolaryngology 2003, 32, 146-150.<br />

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