Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases

Abstract

PurposeThe aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases.ProceduresWag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [18F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression.Results5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [18F]FLT SUVmean and SUVmax were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUVmax at days −1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [18F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats.ConclusionThis study suggests that 5-FU treatment induces a flare in [18F]FLT uptake of responsive CC531 tumors in the liver, while the ADCmean did not change significantly. Future studies in larger groups are warranted to further investigate whether [18F]FLT PET can discriminate between disease progression and treatment response.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1021-2) contains supplementary material, which is available to authorized users.

Curcumin Reduces Colorectal Cancer Cell Proliferation and Migration and Slows In Vivo Growth of Liver Metastases in Rats

“…On the other hand, we analyzed tumor response after 28 days, which means that our results and those of Maneikyte are not fully scalable. Finally, our results match those reported by Heskamp and colleagues [ 66 ]. They induced tumor implants by injecting CC531 cells, which were then treated with four cycles of 5-FU at different doses (15, 30, and 60 mg/kg).…”

Diffusion weighted magnetic resonance imaging (DW-MRI) as a non-invasive, tissue cellularity marker to monitor cancer treatment response

“…Nuclei counts are calculated as number of nuclei per ROI area from five different ROIs in tumor slide in all groups. The depicted binary images are only for visualization and not does not resemble the ROI used for data analysis studies [29][30][31]. To use DW-MRI to determine patient outcomes in a clinical setting, a standardized protocol for result validation is mandatory [32].…”

Enhanced Therapeutic Efficacy of the Nanoscale Fluoropyrimidine Polymer CF10 in a Rat Colorectal Cancer Liver Metastasis Model

“…We then evaluated the potential of CF10 to reduce the progression of liver tumor mass in the CC531 WAG/Rij rat syngeneic orthotopic CRLM model (Figure 5). As described previously [5,19], the subcapsular injection of CC531 rat CRC tumor cells into a hepatic lobe results in a liver-specific tumor mass that models CRLM for evaluating novel therapies. Tumor masses were identified using a fluorescent RGD peptide that binds to integrin α v β 3 [24], as luciferase expression (Figure S2) was not maintained in CC531 cells in vivo following tumor formation.…”

“…We used a modified clonogenic assay to demonstrate whether CF10 displayed improved potency relative to 5-FU in a rat colon carcinoma cell line, CC531, and we showed whether it was a potent inducer of apoptotic cell death using a live/dead assay. The CC531 cell line is of interest for evaluating potential new agents for improved CRLM treatment because it has been established as a rodent CRLM model for sub-capsular injection into the livers of syngeneic WAG/Rij rats [5,19]. Mechanistically, CF10 is more effective than 5-FU at activating biomarkers of replication stress (e.g., pRPA and pChk1), as assessed by Western blots, and causing DNA doublestrand breaks (DSBs), consistent with the established TS/Top1 dual-targeting mechanism.…”