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The correlation of plasma proteins binding capacity and flavopiridol cellular and clinical trial studies

DOI: 10.3233/BSI-170165 DOI Help

Authors: Daniel P. Myatt (Diamond Light Source; ISIS Spallation Neutron Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biomedical Spectroscopy And Imaging , VOL 6 , PAGES 59 - 73

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 1681 , 2074

Open Access Open Access

Abstract: Previous clinical research has suggested high-affinity binding of flavopiridol (FLAP) to human blood serum proteins, specifically either human serum albumin (HSA) or human alpha-1-acid glycoprotein (hAGP), when compared to fetal bovine serum albumin (BSA) or bovine alpha-1-acid glycoprotein (bAGP) used in pre-clinical assays. This high-affinity binding was suggested as the reason for its poor human clinical trial performance as a treatment for chronic lymphocytic leukaemia (CLL). Using three biophysical techniques, specifically circular dichroism (CD), isothermal calorimetry (ITC) and fluorescence spectroscopy, I show that FLAP does not have an overly high-affinity for either fetal BSA, HSA, bAGP or hAGP. I therefore suggest an alternate hypothesis that models the albumin and alpha-1-acid glycoprotein (AGP) binding sites at the different protein concentrations used in the fetal bovine pre-clinical assay and human physiological conditions. I use analytical ultracentrifugation (AUC) experiments to determine the validity of the theoretical models. The models can also be altered to account for the elevated AGP levels and reduced albumin levels seen in human cancer patients. Major differences in the concentrations of free available FLAP are observed between the fetal bovine pre-clinical model and human physiological conditions. A number of recommendations can therefore be made on how future pre-clinical assay studies should be conducted.

Journal Keywords: Cancer; drug binding; serum albumin; alpha-1-acid glycoprotein; flavopiridol

Subject Areas: Medicine, Technique Development, Biology and Bio-materials

Instruments: B23-Circular Dichroism

Added On: 08/10/2017 22:20

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