Oxaliplatin (1-trans)1,2- diaminocyclohexaneoxalatoplatinum (II)is a second generation platinum compound that has shown significant promise in European clinical trials because of efficacy against cisplatin-resistant tumors. (1) The applicant has developed HPLC techniques for resolving and quantitating the major diaminocyclohexane (dach)-Pt biotransformations of oxaliplatin. He plans to study the stability and mechanism(s) of displacement of the oxalato leaving ligand in plasma and the intracellular biotransformations of oxaliplatin. These studies will characterize the mechanisms and kinetics for activation of oxaliplatin and provide valuable information for the identification of biotransformation products and pathways in a companion clinical study of oxaliplatin pharmacokinetics. (2) Neurotoxicity is the dose-limiting toxicity for oxaliplatin and is likely to be the most serious impediment to its widespread clinical acceptance. Thus, the applicant proposes to: a) determine the dose of oxaliplatin which causes significant neurotoxicity by behavioral and morphometric assays in Wistar rats; b) test the effect of the protective agents ORG2766, WR-2721 and glutathione on oxaliplatin neurotoxicity in this model; c) test the effect of the same agents on oxaliplatin efficacy against the Walker 256 tumor. These data should allow selection of those protective agents which offer the greatest protection against oxaliplatin neurotoxicity with the least alteration of its efficacy. (3) The characteristics of Pt compounds which determine the extent of their neurotoxicity are not well defined. The applicant plans to compare the neurotoxicity of cisplatin, ormaplatin, oxaliplatin and related Pt compounds in vivo and with cultures of dorsal root ganglia in vitro. These experiments should provide a: (a) quantitative comparison of the neurotoxicity of all three Pt drugs; (b) working model for which characteristics of these Pt compounds (hydrophobicity, carrier ligand, isomer of carrier ligand, or oxidation state of Pt) are most closely related to their neurotoxicity; and (c) rationale for design of Pt compounds with reduced neurotoxic potential.
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