Mechanisms of reaction of L-methionine with carboplatin and oxaliplatin in different media: a comparison with cisplatin.
The activity of platinum compounds is dependent on nucleophile substitution reactions. In this paper, we study the reactivity of L-met with carboplatin, oxaliplatin and cisplatin by following with HPLC-UV the concentration of L-met and by characterizing the resulting adducts with LC-MS. In the absence of NaCl, in water, the initial rate at which L-met concentration decreases with cisplatin, oxaliplatin and carboplatin is 0.25 +/- 0.007, 0.057 +/- 0.01 and 0.17 +/- 0.02 mM h(-1), respectively. In phosphate buffer this rate is 0.056 +/- 0.009 for cisplatin, 0.019 +/- 0.001 and 0.13 +/- 0.02 for carboplatin and oxaliplatin, respectively. Reactions of L-met with cisplatin occurred via its conversion into monoaqua species in water and into phosphato-derivatives (AP) in phosphate buffer but finally the same methionine-platinum adducts M2 [(NH3)2(met)]Pt, M4 and M5 [(met)2]Pt were characterized. Reaction of carboplatin with L-met occurred via the formation of M0 [(NH3)2(met)(CBDCA)]Pt whose structure is consistent with the direct interaction of L-met with carboplatin. However, the same final products as those found with cisplatin were characterized. The reaction of oxaliplatin with L-met proceeded through a mechanism similar to that of carboplatin to give M7 [(met)(DACH)]Pt. In the presence of NaCl, cisplatin directly reacted with L-met to yield at least five methionine-platinum adducts. The reaction of carboplatin gave the same adducts suggesting its transformation into cisplatin. The reaction of oxaliplatin with L-met occurred via the formation of aquated species A [(OH)(Cl)(DACH)]Pt which readily underwent reaction with L-met to form M6 [(met)(Cl)(DACH)]Pt and M7. This study shows that the reactivity of cisplatin, carboplatin and oxaliplatin is dependent on the media in which they occur. The discrepancy between their reactions with L-met could partly explain their therapeutic differences.
Heudi
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O
Laboratoire de Pharmacologie et de Toxicologie, Centre Hospitalier Universitaire, Angers, France.
Mercier-Jobard
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Cailleux
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A
Allain
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P
D000970:Antineoplastic Agents / Q000737:chemistry*; D002021:Buffers; D016190:Carboplatin / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000737:chemistry*; D004355:Drug Stability; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000077150:Oxaliplatin; D010710:Phosphates; D013056:Spectrophotometry, Ultraviolet; D014867:Water
D000970:Antineoplastic Agents; D002021:Buffers; D009944:Organoplatinum Compounds; D010710:Phosphates; D000077150:Oxaliplatin; D014867:Water; D008715:Methionine; D016190:Carboplatin; D002945:Cisplatin