Change of Apoptosis and Glucose Metabolism in Lung Cancer Xenografts during Cytotoxic and Anti-Angiogenic Therapy Assessed by Annexin V Based Optical Imaging and 18F-FDG-PET/CT

Abstract

Aim of the Study. To compare Annexin V-based optical apoptosis imaging with the assessment of the glucose metabolism using 18F-FDG-PET/CT for monitoring the response to cytotoxic (carboplatin) and anti-angiogenic (sunitinib) therapy. Methods. For apoptosis imaging, the near-infrared probe Annexin Vivo750 was used in combination with fluorescence molecular tomography and microcomputed tomography (FMT/µCT). Glucose metabolism was assessed using 18F-FDG-PET/CT. Five groups of nude mice bearing lung cancer xenografts (A549) were investigated: (i) untreated controls and two groups after (ii) cytotoxic (carboplatin) or (iii) anti-angiogenic (sunitinib) treatment for four and nine days, respectively. Imaging data were validated by immunohistochemistry. Results. In response to carboplatin treatment, an inverse relation was found between the change in glucose metabolism and apoptosis in A549 tumors. Annexin Vivo showed a continually increasing tumor accumulation, while the tumor-to-muscle ratio of 18F-FDG continuously decreased during therapy. Immunohistochemistry revealed a significantly higher tumor apoptosis ( p = 0.007 ) and a minor but not significant reduction in vessel density only at day 9 of carboplatin therapy. Interestingly, during anti-angiogenic treatment there was an early drop in the tumor-to-muscle ratio between days 0 and 4, followed by a subsequent minor decrease (18F-FDG tumor-to-muscle-ratio: 1.9 ± 0.4; day 4: 1.1 ± 0.2; day 9: 1.0 ± 0.2; p = 0.021 and p = 0.001 , respectively). The accumulation of Annexin Vivo continuously increased over time (Annexin Vivo: untreated: 53.7 ± 36.4 nM; day 4: 87.2 ± 53.4 nM; day 9: 115.1 ± 103.7 nM) but failed to display the very prominent early induction of tumor apoptosis that was found by histology already at day 4 (TUNEL: p = 0.0036 ) together with a decline in vessel density (CD31: p = 0.004 ), followed by no significant changes thereafter. Conclusion. Both molecular imaging approaches enable visualizing the effects of cytotoxic and anti-angiogenic therapy in A549 tumors. However, the early and strong tumor apoptosis induced by the anti-angiogenic agent sunitinib was more sensitively and reliably captured by monitoring of the glucose metabolism as compared to Annexin V-based apoptosis imaging.

Fabricating niosomal-PEG nanoparticles co-loaded with metformin and silibinin for effective treatment of human lung cancer cells

“…To evaluate the anticancer effect of drugs, an apoptosis assay can be performed ( 59 ). Apoptosis is a specifically programmed signaling pathway that induces cell death.…”

Pattern of F-18 FDG Uptake in Colon Cancer after Bacterial Cancer Therapy Using Engineered Salmonella Typhimurium: A Preliminary In Vivo Study

“…However, BCT mechanisms are not simply limited to apoptosis. A recent study investigating apoptosis imaging tracers reported that FDG was more reliable and sensitive for evaluating therapeutic effects [40]. The authors of this study reported that tumor apoptosis, induced by an antiangiogenic agent, was more sensitively and reliably monitored by FDG when compared with Annexin V-based apoptosis imaging [40].…”

“…A recent study investigating apoptosis imaging tracers reported that FDG was more reliable and sensitive for evaluating therapeutic effects [40]. The authors of this study reported that tumor apoptosis, induced by an antiangiogenic agent, was more sensitively and reliably monitored by FDG when compared with Annexin V-based apoptosis imaging [40]. Furthermore, FDG uptake in malignant tumors was influenced not only by cancer cells but also cells in the tumor microenvironment [41–43].…”