3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer
3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer(527 views) Zannetti A, Iommelli F, Speranza A, Salvatore M, Del Vecchio S
J Nucl Med (ISSN: 1535-5667, 0161-5505, 1535-5667electronic), 2012 Mar 1; 53(3): 443-450.
Keywords: 18f-Flt, Egfr, Lung Cancer, Pet Ct, Fluorothymidine F 18, Cl 387 785, Epidermal Growth Factor Receptor Kinase Inhibitor, Erlotinib, Ki 67 Antigen, N [4 (3 Bromoanilino) 6 Quinazolinyl] 2 Butynamide, Navitoclax, Unclassified Drug, Wz 4002, Dideoxynucleoside Derivative, Aniline Derivative, Antineoplastic Agent, Diagnostic Agent, Protein Bcl X, Protein Kinase Inhibitor, Quinazoline Derivative, Radiopharmaceutical Agent, Sulfonamide, Animal Experiment, Animal Model, Animal Tissue, Apoptosis, Article, Cancer Cell Culture, Cell Cycle Arrest, Cell Cycle G1 Phase, Cell Cycle S Phase, Computer Assisted Emission Tomography, Concentration Response, Controlled Study, Dose Response, Drug Efficacy, Drug Megadose, Drug Resistance, Drug Sensitivity, Drug Tumor Level, Gene Mutation, Human, Human Cell, Image Analysis, Immunohistochemistry, Isotope Labeling, Low Drug Dose, Lung Non Small Cell Cancer, Mouse, Nonhuman, Priority Journal, Quantitative Study, Tumor Xenograft, Bagg Albino Mouse, Cell Proliferation, Drug Antagonism, Drug Effect, Female, Image Processing, Lung Tumor, Methodology, Scintiscanning, Tumor Cell Line, Western Blotting, Aniline Compounds, Bcl-X Protein, Carcinoma, Non-Small-Cell Lung, Computer-Assisted, Lung Neoplasms, Inbred Balb C, Positron-Emission Tomography And Computed Tomography, Aniline Compounds Therapeutic Use, Antineoplastic Agents Therapeutic Use, Apoptosis Drug Effects, Non-Small-Cell Lung Drug Therapy Radionuclide Imaging, Cell Proliferation Drug Effects, Dideoxynucleosides Diagnostic Use, Lung Neoplasms Drug Therapy Radionuclide Imaging, Multimodal Imaging Methods, Protein Kinase Inhibitors Therapeutic Use, Quinazolines Therapeutic Use, Radiopharmaceuticals Diagnostic Use, Epidermal Growth Factor Antagonists, Sulfonamides Therapeutic Use, X-Ray Computed, Bcl-X Protein Antagonists,
Affiliations: *** IBB - CNR ***
Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
Department of Biomorphological and Functional Sciences, University of Naples Federico II, Edificio 10, Via S. Pansini 5, 80131 Naples, Italy
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3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer
UNLABELLED: Epidermal growth factor receptor (EGFR) mutational status, activation of downstream signaling, and effective apoptotic cascade are all factors that may affect the tumor response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Here we test whether 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT can provide clues for the selection of patients with NSCLC as candidates for treatment with reversible and irreversible EGFR TKIs or combination treatment with Bcl-x(L) inhibitors.; METHODS: HCC827, H1975, and H1650 NSCLC cells were subcutaneously injected into flanks of nude mice. Tumor-bearing animals were treated daily for 3 d by oral gavage with erlotinib at 50 and 150 mg/kg, CL-387,785 (an irreversible EGFR TKI) at 50 mg/kg, WZ4002 (a more potent irreversible EGFR TKI) at 25 and 50 mg/kg, ABT-263 (a Bcl-x(L) inhibitor) at 6.25 mg/kg, and a combination of erlotinib (50 mg/kg) and ABT-263 (6.25 mg/kg). Imaging studies were performed before and after 3 d of treatment by intravenous injection of 7.4 MBq of (18)F-FLT and small-animal PET/CT of animals at 1 h after injection. Quantitative analysis of reconstructed images of baseline and posttreatment scans was performed, and the percentage change in (18)F-FLT uptake in each animal was determined. Tumor sections were tested for Ki67 immunostaining and the percentage of apoptotic cells.; RESULTS: Sensitive tumors (HCC827) showed mean decreases in (18)F-FLT uptake of 45% and 28% with high- and low-dose regimens of erlotinib, respectively. Resistant NSCLC cells bearing a T790M mutation (H1975) showed mean increases in (18)F-FLT uptake of 27% and 33% with high and low doses of erlotinib, respectively. Treatment with CL-387,785, low-dose WZ4002, and high-dose WZ4002 caused mean decreases in tracer uptake of 21%, 26%, and 36%, respectively. NSCLC cells that were resistant because of dysregulation of Bcl-2 family members (H1650) showed mean reductions in (18)F-FLT uptake of 49% and 23% with high and low doses of erlotinib, respectively, whereas the addition of ABT-263 did not affect tracer uptake but significantly increased the percentage of apoptotic cells in tumor sections.; CONCLUSION: PET/CT with (18)F-FLT may contribute to the selection of patients who may benefit from treatment with reversible and irreversible EGFR TKIs and may provide clues about which patients with NSCLC may be candidates for combination treatment with erlotinib and Bcl-x(L) inhibitors.
3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer
3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer