Discontinuous drug binding to proteins: binding of an antineoplastic benzyl styryl sulfone to albumin and enzymes in vitro and in phase I clinical trials.
Sodium (E)-{N-[2-methyloxy-5-(2',4',6'-trimethoxy-styrylsulfonyl) methylenephenyl]amino}acetate (C(21)H(24)NNaO(8)S, ON 01910.Na) is a novel, synthetic benzyl styryl sulfone, currently in phase I clinical trials in cancer patients. Our objective was to use electrospray mass spectrometry to determine, in intact complexes, the number of drug molecules bound to albumin and selected enzymes. Native and recombinant albumin incubated with the drug, at various molar ratios, revealed simultaneous and discontinuous progression of drug binding, yielding intact albumin-drug complexes containing up to 22 drug molecules. Comparable complex protein-drug patterns were obtained for several enzymes, e.g., carbonic anhydrase. Intact albumin-ON 01910 complexes were also found in all patient samples. The drug-binding profiles were comparable, but not identical, for increasing sampling times and different doses (400-1700 mg/m(2)). We concluded that the techniques developed are capable of detecting the simultaneous formation of intact protein-drug complexes and of determining the number of drug molecules bound to proteins. The results enhance our hypothesis that drug binding may lead to conformational changes in proteins that, in turn, account for the exclusion of specific binding complexes and may influence protein behavior and activity. Application of these techniques reveals new insights about the nature of the antineoplastic drug ON 01910 in patient plasma, and the information obtained may have significance in understanding drug delivery to tumors.
Cho
Sool Yeon
SY
Tisch Cancer Institute and Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029-6574, USA.
Ohnuma
Takao
T
Silverman
Lewis R
LR
Holland
James F
JF
Roboz
John
J
D000418:Albumins / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D017321:Clinical Trials, Phase I as Topic; D004798:Enzymes / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D013450:Sulfones / Q000378:metabolism*
D000418:Albumins; D000970:Antineoplastic Agents; D004798:Enzymes; D013450:Sulfones; C507134:ON 01910; D005998:Glycine