99m Tc-Duramycin SPECT Imaging of Early Tumor Response to Targeted Therapy: A Comparison with 18 F-FDG PET

J Nucl Med. 2017 Apr;58(4):665-670. doi: 10.2967/jnumed.116.182014. Epub 2016 Nov 22.

Abstract

Molecular imaging of cell death may provide a detailed readout of the cellular response to novel therapies and prognostic information on tumor treatment efficacy, assisting in the design of individualized therapy. We compared the predictive power of cell death imaging using 99mTc-duramycin with the current gold standard 18F-FDG for treatment response evaluation after targeted therapy. Methods: Early therapy response evaluation was assessed by 99mTc-duramycin SPECT and 18F-FDG PET imaging in treatment-sensitive COLO205 and treatment-resistant HT29 human colorectal cancer xenografts 24 h after a single dose of conatumumab or IgG1 control. The specificity of 99mTc-duramycin for apoptosis was assessed using 99mTc-linear duramycin control radiotracer. Radiotracer uptake was validated ex vivo by γ-counting and autoradiography and compared with cleaved caspase-3 (CC3) activation and DNA fragmentation (TdT-mediated dUTP nick-end labeling [TUNEL]). Data were analyzed with the Student t test and Pearson correlation. All statistical tests were 2-sided. Results: COLO205 tumor uptake of 99mTc-duramycin was increased 7-fold from baseline in conatumumab- versus IgG1-treated control mice (P < 0.001), in good correlation with histologic analysis of apoptosis (CC3, r = 0.842, and TUNEL, r = 0.894; P < 0.001). No response was detected in HT29 tumors. No change in 99mTc-linear duramycin uptake could be detected in COLO205 tumors after treatment, indicating specificity of the 99mTc-duramycin tumor signal. 18F-FDG uptake was not significantly increased from baseline in conatumumab- versus IgG1-treated COLO205 and HT29 tumor-bearing mice (P = 0.104 and 0.779, respectively) and did not correlate with immunohistochemical evidence of apoptosis. Conclusion: We have demonstrated that 99mTc-duramycin specifically accumulates in apoptotic tumors in which 18F-FDG was not able to differentiate responding from nonresponding tumors early after treatment. 99mTc-duramycin holds promise as a noninvasive imaging radiotracer for early treatment evaluation in the clinic.

Keywords: 99mTc-duramycin SPECT; cell death imaging; colorectal cancer; response evaluation; targeted therapy.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Apoptosis
  • Bacteriocins* / metabolism
  • Bacteriocins* / pharmacokinetics
  • Biological Transport
  • Colonic Neoplasms / diagnostic imaging*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Fluorodeoxyglucose F18*
  • HT29 Cells
  • Humans
  • Mice
  • Molecular Targeted Therapy*
  • Organotechnetium Compounds* / metabolism
  • Organotechnetium Compounds* / pharmacokinetics
  • Positron-Emission Tomography*
  • Time Factors
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon*
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Bacteriocins
  • Organotechnetium Compounds
  • technetium 99m HYNIC-duramycin
  • Fluorodeoxyglucose F18
  • conatumumab