Imaging the life and death of tumors in living subjects: Preclinical PET imaging of proliferation and apoptosis

Abstract

Cancer is characterized by deregulation of cell proliferation and altered cell death apoptosis, which constitutes, in almost all instances, the minimal common platform upon which all neoplastic evolution occurs. The most implicit and clinically attractive anticancer strategies, therefore, consist of eliminating tumor cells by preventing their expansion and ultimately inducing cell death apoptosis. In this context, the non-invasive molecular assessment of tumor cell proliferation and apoptosis status using PET imaging constitutes a major strategy in preclinical studies to assess the efficacy of new anticancer therapeutics using small animal PET imaging, and in clinical settings for the monitoring of treatment responses in patients. For this purpose, a variety of PET tracers targeting specific molecular entities allowing the non-invasive measurement of biological processes, including cell proliferation and apoptosis, are under development for use in preclinical studies and clinical trials to non-invasively image in vivo the lifeline of tumors.

Biomarkers and Molecular Probes for Cell Death Imaging and Targeted Therapeutics

“…Lipophilic phosphonium cations are known to penetrate healthy cells and accumulate at mitochondrial membranes that have a strongly negative transmembrane potential (62). During apoptosis, the electrochemical proton gradient across the inner mitochondrial membrane collapses causing a reduction in phosphonium cation tracer levels (63). The 18 F-fluorobenzyl triphenylphosphonium cation ( 18 F-FBnTP) has been investigated as a PET imaging probe to detect alterations in mitochondrial membrane potential in vitro and in vivo.…”

Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients

“…Noninvasive imaging techniques which evaluate the entire tumor burden can overcome these obstacles and offer serial evaluation of tumor metabolic activity in vivo . 2-Deoxy-2- 18 F]fluoro- d -glucose positron emission tomography (FDG PET) holds promise as a marker of tumor glycolysis that may parallel Ki-67 [10,11] as an indirect measure of cell proliferation [12]. Serial FDG PET can serve as a pharmacodynamic marker of response to chemotherapy in several tumors, including breast [13-15].…”

Assessment of Response to Therapy

“…Preliminary in vitro studies have demonstrated that the level of 18FMAU uptake is proportional to the level of DNA synthesis and the rate of tumor proliferation (Nishii et al 2008;Sun et al 2005). Further studies are needed to evaluate the potential of 18FMAU as a PET imaging tracer of cell proliferation and its utility in monitoring treatment (Nguyen and Aboagye 2010).…”

“…Another radiotracer for imaging cell proliferation is 18FMAU [1-(2 0 -deoxy-2 0 -fluoro-beta-D-arabinofuranosyl)thymine], which is a thymidine analog that can be phosphorylated and subsequently incorporated into DNA, and because of minimal marrow uptake and urinary excretion, appears to be promising for studying bone metastasis and the pelvic region (Nguyen and Aboagye 2010). Preliminary in vitro studies have demonstrated that the level of 18FMAU uptake is proportional to the level of DNA synthesis and the rate of tumor proliferation (Nishii et al 2008;Sun et al 2005).…”