Detecting functional changes with [18F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy

Abstract

BackgroundThe multitargeting tyrosine kinase inhibitor (TKI) sunitinib is currently the first-line drug therapy for metastasizing renal cell carcinoma (RCC). TKIs have profound effects on tumor angiogenesis, leading to modifications of the tumor microenvironment. The goal of this study was to determine whether these treatment-induced changes can be detected with [18F]FAZA.MethodsThe present study utilized positron emission tomography (PET) to analyze tumor oxygenation status during and after sunitinib therapy in the murine Caki-1 RCC tumor model. Dynamic and static scans were performed, as well as ex vivo biodistributions at 3 h post injection (p.i.). Immunohistochemical analysis of tumor tissue was carried out for the quantification of pimonidazole binding and the hypoxia-associated factors CD-31, Ki-67, and Von Willebrand factor (VWF). In addition, in vitro cellular uptake studies were done to analyze the direct effects of sunitinib on the Caki-1 cells.ResultsDuring therapy with sunitinib (40 mg/kg/day), uptake of [18F]FAZA into Caki-1 mice decreased by 46 ± 5% (n = 4; 5 days) at 3 h post injection (p.i.) during the first study and 22 ± 5% (n = 8; 9 days) during the long-term study, indicating a decrease in the tumor's hypoxia level. However, when drug therapy was stopped, this effect was reversed completely, and the tumor [18F]FAZA uptake increased to 126 ± 6% (n = 6) of the control tumor uptake, indicative of an even higher level of tumor hypoxia compared to the therapy starting point. Sunitinib had no direct effect on [18F]FAZA uptake into Caki-1 cells in vitro.Conclusion[18F]FAZA PET could be used to monitor drug response during sunitinib therapy in RCC and may guide combination therapies based on the tumor's hypoxia status.

Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer—effects of hypoxia

“…In a patient study using [ 18 F]FMISO as an hypoxia-targeting radiotracer, no correlation to HIF1a expression was observed in primary BC lesions, which was ascribed to an induction of HIF1a by alternative pathways and stimuli [e.g., growth factors, cytokines, and hormones (30)]. With the use of [ 18 F]FAZA in a human renal carcinoma model, good correlation between tumor uptake and pimonidazole staining was detected (31). It still needs to be established whether [ 18 F]FMISO or [ 18 F]FAZA shows a better correlation between HIF1a expression and radiotracer uptake in patient-derived BC lesions.…”

Choosing the right cell line for renal cell cancer research

“…Ectopic xenograft models of athymic nude mice with various genetic backgrounds have been extensively used for studying established RCC lines, including 769-P, 786-O, Caki-1, SK-RC-38, SK-RC-42, SK-RC-44, SK-RC-45, SK-RC-46, and others [17, 55, 169–173]. As summarized in Additional file 1: Table S1, most of the cell lines described in this article were proven to be tumorigenic in nude mice.…”

“…As summarized in Additional file 1: Table S1, most of the cell lines described in this article were proven to be tumorigenic in nude mice. The implanted tumors normally become palpable within 5 days and reach a volume of 100 mm 3 in 2 weeks [169–171]. Implanted established cell lines xenografted into nude mice preserve essentially the same histology as the primary tumors [174].…”

Biological characterization of novel nitroimidazole‐peptide conjugates in vitro and in vivo

“…In normoxic tissue, the resulting radical anion is re-oxidized, whereas in hypoxic regions, the radical anion undergoes further reduction steps ultimately leading to final products that are covalently linked to macromolecules and accumulate in hypoxic tissue [7]. Until now, radiolabeled nitroimidazoles, like iodoazomycinarabinoside [8,9], fluormisonidazole [10,11], or fluorazomycinarabinoside [12], have been successfully applied in preclinical and clinical studies.…”