Combining [11C]-AnxA5 PET imaging with serum biomarkers for improved detection in live mice of modest cell death in human solid tumor xenografts

PLoS One. 2012;7(8):e42151. doi: 10.1371/journal.pone.0042151. Epub 2012 Aug 1.

Abstract

Background: In vivo imaging using Annexin A5-based radioligands is a powerful technique for visualizing massive cell death, but has been less successful in monitoring the modest cell death typically seen in solid tumors after chemotherapy. Here we combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model.

Methodology/principal findings: Modest cell death was induced by doxorubicin in a mouse xenograft model with human FaDu head and neck cancer cells. PET imaging was based on (11)C-labeled Sel-tagged Annexin A5 ([(11)C]-AnxA5-ST) and a size-matched control. 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG) was utilized as a tracer of tissue metabolism. Serum biomarkers for cell death were ccK18 and K18 (M30 Apoptosense® and M65). Apoptosis in tissue sections was verified ex vivo for validation. Both PET imaging using [(11)C]-AnxA5-ST and serum ccK18/K18 levels revealed treatment-induced cell death, with ccK18 displaying the highest detection sensitivity. [(18)F]-FDG uptake was not affected by this treatment in this tumor model. [(11)C]-AnxA5-ST gave robust imaging readouts at one hour and its short half-life made it possible to perform paired scans in the same animal in one imaging session.

Conclusions/significance: The combined use of dynamic PET with [(11)C]-AnxA5-ST, showing specific increases in tumor binding potential upon therapy, with ccK18/K18 serum measurements, as highly sensitive markers for cell death, enabled effective assessment of modest therapy-induced cell death in this mouse xenograft model of solid human tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / pharmacology*
  • Apoptosis*
  • Biomarkers, Tumor / metabolism*
  • Carbon Isotopes / pharmacology
  • Carcinoma, Squamous Cell / diagnostic imaging*
  • Carcinoma, Squamous Cell / metabolism*
  • Disease Models, Animal
  • Fluorodeoxyglucose F18 / pharmacology
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Positron-Emission Tomography / methods*
  • Radiography
  • Radiopharmaceuticals
  • Transplantation, Heterologous

Substances

  • Annexin A5
  • Biomarkers, Tumor
  • Carbon Isotopes
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18

Grant support

This work was supported by the Swedish Foundation for Strategic Research (SSF) (RBa08-0067); Governmental Agency for Innovation Systems (VINNOVA) (2009-00179); The Swedish Cancer Society (Cancerfonden) (2009/739 to E.S.J.A.); The Swedish Research Council (2008-2654 to E.S.J.A., 2004-5104 and 2008-3186 to S.S.E.); and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.