2. Author's Information
    Ning Qu
    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, U.S.A.

    Natalia A. Ignatenko
    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, U.S.A.

    Phillip Yamauchi
    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, U.S.A.

    David E. Stringer
    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, U.S.A.

    Corey Levenson
    ILEX Oncology, Inc., 4545 Horizon Hill Blvd, San Antonio, TX 78229, U.S.A.

    Patrick Shannon
    ILEX Oncology, Inc., 4545 Horizon Hill Blvd, San Antonio, TX 78229, U.S.A.

    Scott Perrin
    NOVASEP Inc., Boothwyn, PA 19061, U.S.A.

    Eugene W. Gerner
    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, U.S.A.
  3. Abstract
    Racemic difluoromethylornithine (d/l-DFMO) is an inhibitor of ODC (ornithine decarboxylase), the first enzyme in eukaryotic polyamine biosynthesis. d/l-DFMO is an effective anti-parasitic agent and inhibitor of mammalian cell growth and development. Purified human ODC-catalysed ornithine decarboxylation is highly stereospecific. However, both DFMO enantiomers suppressed ODC activity in a time- and concentration-dependent manner. ODC activity failed to recover after treatment with either l- or d-DFMO and dialysis to remove free inhibitor. The inhibitor dissociation constant (KD) values for the formation of enzyme�inhibitor complexes were 28.3�3.4, 1.3�0.3 and 2.2�0.4 ?M respectively for d-, l- and d/l-DFMO. The differences in these KD values were statistically significant (P<0.05). The inhibitor inactivation constants (Kinact) for the irreversible step were 0.25�0.03, 0.15�0.03 and 0.15�0.03 min?1 respectively for d-, l- and d/l-DFMO. These latter values were not statistically significantly different (P>0.1). d-DFMO was a more potent inhibitor (IC50~7.5 ?M) when compared with d-ornithine (IC50~1.5 mM) of ODC-catalysed l-ornithine decarboxylation. Treatment of human colon tumour-derived HCT116 cells with either l- or d-DFMO decreased the cellular polyamine contents in a concentration-dependent manner. These results show that both enantiomers of DFMO irreversibly inactivate ODC and suggest that this inactivation occurs by a common mechanism. Both enantiomers form enzyme�inhibitor complexes with ODC, but the probability of formation of these complexes is 20 times greater for l-DFMO when compared with d-DFMO. The rate of the irreversible reaction in ODC inactivation is similar for the l- and d-enantiomer. This unexpected similarity between DFMO enantiomers, in contrast with the high degree of stereospecificity of the substrate ornithine, appears to be due to the ?-substituent of the inhibitor. The d-enantiomer may have advantages, such as decreased normal tissue toxicity, over l- or d/l-DFMO in some clinical applications.
    Keywords
    difluoromethylornithine enantiomer, enzyme inactivation parameter, ornithine decarboxylase, polyamine
    DOI: 10.1042/bj20030382
    ADLID: 55628-v4
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  1. Keywords
    difluoromethylornithine enantiomer enzyme inactivation parameter ornithine decarboxylase polyamine
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