Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) Pharmacokinetics in FaDu Xenograft Tumors and Correlation With Microscopic Markers of Hypoxia

Abstract

Purpose The behavior of 64Cu-ATSM in hypoxic tumors was examined through a combination of in vivo dynamic PET imaging, and ex vivo autoradiographic and histological evaluation using a xenograft model of H&N squamous cell carcinoma. Methods and Materials 64Cu-ATSM was administered during dynamic PET imaging, and temporal changes in 64Cu-ATSM distribution within tumors were evaluated for at least 1 h and up to 18 h. Animals were sacrificed at either 1 h (cohort A) or after 18 h (cohort B) post-injection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment sub-regions was conducted by immunohistochemical staining for markers of hypoxia (Pimonidazole Hydrochloride) and blood flow (Hoechst-33342). Results Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (Ki) constant was twelve-fold that of muscle, while the distribution volume (Vd) was five-fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18 h course of imaging. However, no spatial changes in 64Cu-ATSM distribution occurred in PET imaging after 20 minutes post-injection. Microscopic intratumoral distribution of 64Cu-ATSM and Pimonidazole were not correlated at 1 h or after 18 h post-injection, and neither was 64Cu-ATSM and Hoechst-33342. Conclusions The oxygen partial pressures at which 64CuATSM and Pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Nonetheless, researchers have shown 64Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer.

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

“…Also, different relationships between pO 2 and the spatial distribution of 64 CuCl 2 and 64 Cu-ATSM were found. The level of tumor uptake and tumor-to-background ratios of both 64 Cu-ATSM and 64 CuCl 2 found in this study seems to be lower than has previously been reported (14,20,33). However, during the 1-h dynamic scans, the tumor-to-muscle ratios of both 64 Cu-ATSM and 64 CuCl 2 continued to increase and did not reach a plateau.…”

“…A previous study on nude rats with FaDu tumors found no correlation between hypoxia marker, pimonidazole, and intratumoral spatial distribution of 64 Cu-ATSM 1 and 18 h after injection (20). In contrast, another study using the same tumor model found that there was no temporal change in the intratumoral distribution of 64 Cu-ATSM early (2 h) or late (16 h) after injection and that pO 2 probe measurements from different tumor sections corroborated well with PET images (21).…”

“…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.…”

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 …”

“…In oncology, [Cu]ATSM has been evaluated both preclinically and clinically. This tracer shows favorable kinetics with rapid uptake in hypoxic tissue and fast clearance from normoxic tissues, enabling imaging within 30 min after injection [66,67] . However, the exact uptake mechanism of [Cu]ATSM is still under debate [63,68,69] and several preclinical studies have shown that [Cu]ATSM uptake depends on tumor type and other characteristics than hypoxia alone [70][71][72][73][74][75][76] .…”