Comparative neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products utilizing a rat dorsal root ganglia in vitro explant culture model

Pur pose: Neurotoxicity is one of the major toxicities of platinum-based an ticancer drugs, especially oxaliplatin and ormaplatin. It has been postulat ed that biotransformation products are likely to be responsible for the tox icity of platinum drugs. In our preceding pharmacokinetic study, both oxali platin and ormaplatin were observed to produce the same types of major plas ma biotransformation products. However, while the plasma concentration of o rmaplatin was much lower than that of oxaliplatin at an equimolar dose, one of their common biotransformation products, Pt(dach)Cl-2, was present at 2 9-fold higher concentrations in the plasma following the i.v. injection of ormaplatin than of oxaliplatin. Because ormaplatin has severe neurotoxicity and Pt(dach)Cl-2 is very cytotoxic, we have postulated that Pt(dach)Cl-2 i s likely to be responsible for the differences in neurotoxicity between orm aplatin and oxaliplatin. In order to test this hypothesis, we compared the neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation produ cts; Since the dorsal root ganglia (DRGs) have been suggested to be the lik ely targtet for platinum drugs and in vitro DRG explant cultures have been suggested to be a valid model for studying cisplatin-associated neurotoxici ty, our comparative neurotoxicity study was conducted with DRG explant cult ures in vitro. Methods: Based on the previous studies of cisplatin neuro - toxicity, we established our in vitro DRG explant culture utilizing DRGs di ssected from E-19 embryonic rats. Rat DRGs were incubated for 30 min with d ifferent platinum compounds to mimic in vivo exposure conditions; this was by followed by a 48-h incubation in culture medium at 37 degrees C. At the end of the incubation, the neurites were fixed and stained with toluidine b lue, and neurite out-growth was quantitated by phase-contrast microscopy. T he inhibition of neurite outgrowth by platinum compounds was used as an ind icator of in vitro neurotoxicity. Since an in vivo study has indicated that the order of neurotoxicity is ormaplatin > cisplatin greater than or equal to oxaliplatin > carboplatin as measured by morphometric changes to rat DR Gs, we initially validated our DRG explant culture model by comparing the i n vitro neurotoxicity of ormaplatin, cisplatin, oxaliplatin, and carboplati n. After observing the same neurotoxicity rank between this study and a pre vious in vivo study, we further compared the neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products including Pt(dach)Cl-2, Pt (dach)(H2O)Cl, Pt(dach)(H2O)(2), Pt(dach)(Met), and Pt(dach)(GSH) utilizing the DRG explant culture model. Results: Our study indicated that Pt(dach)C l-2 and its hydrolysis products were more potent at inhibiting neurite outg rowth than the parent drugs oxaliplatin and ormaplatin. In contrast, no det ectable inhibition of neurite outgrowth was observed for DRGs dosed with Pt (dach)(Met) and Pt(dach)(GSH). Conclusion: This study suggests that biotran sformation products such as Pt(dach)Cl-2 and its hydrolysis products are mo re neurotoxic than the parent drugs oxaliplatin and ormaplatin. The differe nt neurotoxicity profiles of oxaliplatin and ormaplatin are more likely due to the different plasma concentrations of their common biotransformation p roduct Pt(dach)Cl-2 than to differences in their intrinsic neurotoxicity.