Oxaliplatin Degradation in the Presence of Chloride: Identification and Cytotoxicity of the Monochloro Monooxalato Complex

Abstract

[Pt(dach)oxCl]-, a new transformation product of oxaliplatin, has been identified. Its in vitro cytotoxic effect does not appear to exceed that of oxaliplatin.

Mechanistic Insights into in vitro DNA Adduction of Oxaliplatin

“…This buffer system is similar to one (50 mM NaCl, 10 mM HEPES buffer at pH 7.4 and 37 o C) in which oxaliplatin degradation was characterized to occur at a few percent per hour to form chlorinated species. 10 The initial concentration of oxaliplatin was 12.4 µg/mL (33.4 nmol, 33.4 µM), which contained 13.4 dpm (96.8 fmol) of [ Figure 3 for specific time points sampled), and were immediately adjusted to 0.5 M NaCl and frozen in liquid nitrogen. For AMS sample preparation, the samples were thawed on ice and the DNA was isolated at 4 o C by ethanol precipitation and air dried.…”

“…the concentration of the DNA target remains in constant vast excess), allowing for the determination of kobs. The chlorination reaction of oxaliplatin is known to be negligibly slow, 10 and the corresponding forms have been ignored in terms of kinetic consideration in this study, leading to a four-step consecutive irreversible pseudo-first-order reaction scheme. The overall rate constant kobs can be used to calculate each rate constant based on the equation of 1/kobs = 1/k1 + 1/k2 + 1/k3 + 1/k4, which can be used to estimate the rate constant k3, when other rate constants k 1 , k 2 and k 4 are known.…”

“…It should be pointed out that in this mechanism chlorination reaction, backward reaction of the first ring-opening step, and acid dissociation of the oxalate monodentate complex are ignored in order to simply understand the mechanism of action for oxaliplatin in the reaction system employed, since 1) the buffer system employed is similar to one (50 mM NaCl, 10 mM HEPES buffer at pH 7.4 and 37 o C) in which oxaliplatin degradation was characterized to occur at a few percent per hour to form chlorinated species, although this chlorination reaction should not be ignored under in vivo conditions, 10 2) the series reaction of the hydrolysis of oxaliplatin is known to obey pseudo-first order kinetics and rate of the formation of diaquated species is very fast compared to that of the formation of diaquated cisplatin or carboplatin species (it should be noted, however, that the reverse reaction of oxaliplatin formation is fast when the oxalate monodentate complex is acidified, although at pH ≥ 12 the conversion of the oxalate monodentate complex back to oxaliplatin is less than 1%), 5(c) and 3) the acid dissociation constant for the oxalate monodentate complex (~5.9 × 10…”

Rákellenes gallium- és platinafém komplexek oldatkémiája, kölcsönhatásuk vérszérum-fehérjékkel és DNS-sel

“…A folyamat leírását tovább bonyolítja, hogy a monoakvakomplex gyűrűzárást követően visszaalakulhat oxaliplatinná, a visszaalalkulás mértéke fiziológiás pH-n jelentős [107,108]. Kloridion jelenlétében a köztitermék deprotonálódását leszámítva ugyanezek a lépések játszódnak le, egy gyors előegyensúly beállását követően viszonylag lassan képződik a dikloridokomplex végtermék [109,110]. A kloridion-mentes közegben lúgos pH-n (pH ≥ 12) meghatározott felezési idők irodalmi adatai (t 1/2(gyűrűnyitás) = 16 perc, t 1/2(2. lépés) = 92 perc) [108] azonban nagyságrendileg sem egyeztethetők össze a mi eredményeinkkel: a méréseink ennél lassabb folyamatokat mutattak.…”

“…Az 5.1.1. ábra alapján elmondható, hogy a hőmérséklet növelése jelentősen gyorsítja a komplexek hidrolízisét. A kloridkoncentráció növelésével a hidrolízis sebessége nő, ez az oxaliplatinról fellelhető irodalmi adatoknak megfelel [109,110]. Kloridion jelenlétében mi is tapasztaltuk a viszonylag gyors előegyensúlyi folyamat lejátszódását az első órában (ld.…”