The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]Fluoromisonidazole positron emission tomography

Abstract

[ 64 Cu]Cu(II)-ATSM (64 Cu-ATSM) and [18F]-Fluoromisonidazole (18 F-FMiso) tumor binding as assessed by positron emisson topography (PET) was used to determine the responsiveness of each probe to modulation in tumor oxygenation levels in the SCCVII tumor model. Animals bearing the SCCVII tumor were injected with 64 Cu-ATSM or 18 F-FMiso followed by dynamic small animal PET imaging. Animals were imaged with both agents using different inspired oxygen mixtures (air, 10% oxygen, carbogen) which modulated tumor hypoxia as independently assessed by the hypoxia marker pimonidazole. The extent of hypoxia in the SCCVII tumor as monitored by the pimonidazole hypoxia marker was found to be in the following order: 10% oxygen > air > carbogen. Tumor uptake of 64 Cu-ATSM could not be changed if the tumor was oxygenated using carbogen inhalation 90 min post-injection suggesting irreversible cellular uptake of the 64 Cu-ATSM complex. A small but significant paradoxical increase in 64 Cu-ATSM tumor uptake was observed for animals breathing air or carbogen compared to 10% oxygen. There was a positive trend toward 18 F-FMiso tumor uptake as a function of changing hypoxia levels in agreement with the pimonidazole data. 64 Cu-ATSM tumor uptake was unable to predictably detect changes in varying amounts of hypoxia when oxygenation levels in SCCVII tumors were modulated. 18 F-FMiso tumor uptake was more responsive to changing levels of hypoxia. While the mechanism of nitroimidazole binding to hypoxic cells has been extensively studied, the avid binding of Cu-ATSM to tumors may involve other mechanisms independent of hypoxia that warrant further study.

PET of Hypoxia and Perfusion with 62Cu-ATSM and 62Cu-PTSM Using a 62Zn/62Cu Generator

“…Our group has shown that the correlation of Cu-ATSM with hypoxia is tumor-dependent in rodent tumor models [17]. Similar findings were recently reported by Matsumoto et al [18], who found differences between the distribution of 64 Cu-ATSM and 18 F-fluoromisonidazole for measuring hypoxia in a murine squamous cell carcinoma model.…”

“…O'Donoghue et al [19] compared early and late imaging of 64 Cu-ATSM with 18 Ffluoromisonidazole in rat tumor models. Although early imaging of 64 Cu-ATSM correlated with 18 F-fluoromisonidazole in the FaDu tumor model, 64 Cu-ATSM needed to be performed much later (16)(17)(18)(19)(20) hours) to achieve a distribution similar to 18 F-fluoromisonidazole in the R3327-AT tumor model. One hypothesis to explain these differences is that the distribution of Cu-ATSM may be limited in certain tumors by reduced delivery of the radiotracer because of poor perfusion.…”

“…Further investigation is needed to determine the efficacy of Cu-ATSM for imaging hypoxia compared with other radiotracers, such as 18 F-fluoromisonidazole and 18 2,3,3,3-pentafluoropropy] acetamide). Our group has shown that the correlation of Cu-ATSM with hypoxia is tumor-dependent in rodent tumor models [17].…”

Positron emission tomography to assess hypoxia and perfusion in lung cancer

“…The short-lived radionuclides can be used for sequential measurements, whereas radionuclides with longer half lives do Table 2 for full names. Lewis et al [133] , Yuan et al [134] , Kersemans et al [135] , Matsumoto et al [136] Ballegeer et al [137] , Bowen et al [138] , Lewis et al [133] , Myerson et al [139] , O'Donoghue et al [72] Ballegeer et al [137] , Hansen et al [140] , Matsumoto et al [136] , McCall et al [66] , O'Donoghue et al [72] , Oh et al [74] , Yuan et al [134] Grigsby et al [141] , Tateishi et al [142] , Valtorta et al [143] , Weeks et al [144] Dence et al [145] , Kersemans et al [135] , Lewis et al [146] , Matsumoto et al [136] , O'Donoghue et al [72] Dehdashti et al [86] , Lohith et al [67] , Wong et al [80] , Zhang et al [81] Chao et al [147] , Dehdashti et al [148] , Dehdashti et al [149] , Dietz et al [150] , Grassi et al [151] , Grigsby et al [141] , Kositwattanarerk et al [152] , Laforest et al [153] , Lewis et al [154] , Minagawa et al [155] , Nyflot et al [156] [ Mahy et al [158] , Mahy et al …”

64Cu-ATSM Reflects pO2 Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with 64CuCl2

“…64 Cu-ATSM has a high tumor-to-background ratio and has shown promising results in small clinical studies, in which the tumor-to-muscle ratio was able to predict treatment outcome (11)(12)(13). However, the robustness of 64 Cu-ATSM as a marker of hypoxia has been questioned, because preclinical studies have reported temporal changes in tumor uptake and cell-type-specific differences in hypoxia selectivity (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Table 1 provides an overview of major studies using 64 Cu-ATSM in small-animal tumor xenograft models.…”