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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055326-06
Application #
2443004
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
1991-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1999-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Luo, F R; Wyrick, S D; Chaney, S G (1999) Comparative neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products utilizing a rat dorsal root ganglia in vitro explant culture model. Cancer Chemother Pharmacol 44:29-38
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Holmes, J; Stanko, J; Varchenko, M et al. (1998) Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. Toxicol Sci 46:342-51
Chaney, S G; Sancar, A (1996) DNA repair: enzymatic mechanisms and relevance to drug response. J Natl Cancer Inst 88:1346-60
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Thompson, D C; Vaisman, A; Sakata, M K et al. (1995) Organ-specific biotransformation of ormaplatin in the Fischer 344 rat. Cancer Chemother Pharmacol 36:439-47
Thompson, D C; Wyrick, S D; Holbrook, D J et al. (1995) Effects of anesthetics on ormaplatin biotransformations in the Fischer 344 rat. Cancer Invest 13:555-7

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