Book of Abstracts - Ruhr-Universität Bochum

P-02
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Degradation of Platinum-Based Anticancer Drugs by Thiosulfate Ions:
an EXAFS Study
Diane Bouvet- Muller, a A. Michalowicz, a S.Crauste-Manciet, b,c and K. Provost a
a Institut de Chimie et des Matériaux Paris Est, ICMPE/SAX, UMR 7182 CNRS-Paris Est, 2 à 8 rue
Henri Dunant, 94320 Thiais, France, b Laboratoire de Pharmacie Galénique, Université Paris V,
75006 Paris, France, c Service de Pharmacie, CHI Poissy Saint Germain en Laye, 78105 Saint
Germain en Laye, France. E-mail: muller@u-pec.fr
Three platinum complexes are currently used worldwide: cisplatin, carboplatin and oxaliplatin. 1
Cisplatin is the most common, and its reactivity has been widely studied. On the contrary, derivatives
of carboplatin and oxaliplatin deserve to be structurally characterized in order to understand their
mode of action and stability in solution. This study takes place in the work carried out by our group on
the behavior of these platinum complexes in presence of various halogen and sulfur ligands. 2-4
These drugs react rapidly with nucleophilic species in solution. Their degradation has two
consequences: in vitro, it can compromise the stability of the drug in solution before administration; in
vivo, the structural modification of these molecules can induce notable changes in their modes of
action. Sulfur nucleophilic ligands are particularly interesting: 5 they play a major role in the
detoxification of the drugs. Particularly, thiosulfate ions are used to prevent nephro- and ototoxicity. 6
This study deals with the reaction of carboplatin and oxaliplatin with thiosulfate. For both drugs, the
reaction products remain in solution. Thus we used X-ray absorption spectroscopy in order to
characterize their structures. Spectra have been recorded for different reaction times (from one hour to
one month) and for different drug/thiosulfate ratios (from 1/2 to 1/40). For a 1/2 ratio at one month of
reaction, we observe the displacement of the carboxylate ligand for both drugs,and a strong similarity
of the signal between 3 and 4 Å. This EXAFS signal can be used as a signature of the Pt-Thiosulfate
binding, in order to model the complete reaction products structures in solution.
On this basis, the spectral and structural evolution as a function of the reaction time on one hand and
of the drug/thiosulfate ratio on the other hand are discussed.
References
1. L.R. Kelland, Nat. Rev. Cancer 2007, 7, 573-584.
2. D.Bouvet, A. Michalowicz, S. Crauste-Manciet, D. Brossard, K. Provost. Inorg. Chem 2006,
45, 3393-3398.
3. D. Bouvet et al. J. Synchr. Rad. 2006, 13, 477-483.
4. K. Provost et al. Biochimie 2009, 91, 1301-1306.
5. J. Reedjik, Chem. Rev. 1999, 99, 2499-2510.
6. D.J. Leitao, B.W. Blakley. Journal of Otolaryngology 2003, 32, 146-150.
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