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Modeling pharmacodynamic response to the poly(ADP-Ribose) polymerase inhibitor ABT-888 in human peripheral blood

Jiuping Ji1, Robert J Kinders, Yiping Zhang

  • 1National Clinical Target Validation Laboratory, National Cancer Institute at Frederick, Frederick, Maryland, United States of America. jijiupi@mail.nih.gov

Plos One
|October 27, 2011
PubMed
Abstract

Insights

Peripheral blood mononuclear cells (PBMCs) can be used to monitor poly(ADP-ribose) (PAR) levels, a marker for poly(ADP-ribose) polymerase (PARP) inhibitor activity. This validated immunoassay in PBMCs shows potential as a surrogate for tumor biopsies in clinical trials.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Poly(ADP-ribose) polymerase (PARP) is crucial for DNA repair.
  • PARP inhibitors show potential in potentiating chemotherapy for cancer treatment.
  • Peripheral blood mononuclear cells (PBMCs) offer a minimally invasive alternative to tumor biopsies for monitoring drug effects.

Purpose of the Study:

  • To validate an immunoassay for quantifying poly(ADP-ribose) (PAR) levels in PBMCs.
  • To assess PBMCs as a surrogate tissue for monitoring PARP inhibitor pharmacodynamics in clinical trials.

Main Methods:

  • Validated a previously established immunoassay for PAR measurement in PBMCs.
  • Quantified PAR levels in PBMCs from healthy volunteers and cancer patients.
  • Assessed ex vivo PBMC response to the PARP inhibitor ABT-888.

Main Results:

  • The PAR immunoassay was successfully validated for PBMC analysis.
  • Baseline PAR levels showed no significant difference between healthy volunteers and cancer patients.
  • Significant intra- and inter-individual variation in PAR levels was observed.
  • Ex vivo treatment with ABT-888 demonstrated variable PAR reduction in PBMCs, with some samples showing insensitivity.

Conclusions:

  • The validated PAR immunoassay in PBMCs supports its use in clinical trials.
  • PBMCs show potential as a pharmacodynamic surrogate for tumor biopsies in PARP inhibitor trials.
  • Further investigation into PARP's role in PBMCs is warranted.

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