Colorectal tumor cells treated with 5-FU, oxaliplatin, irinotecan, and cetuximab exhibit changes in 18F-FDG incorporation corresponding to hexokinase activity and glucose transport.

UNLABELLED: The purpose of this study was to determine therapy-induced changes in 18F-FDG incorporation at the colorectal tumor cell level in response to conventional and novel chemotherapy agents and examine how these changes relate to factors involved in 18F-FDG incorporation. METHODS: SW620 cells were treated with inhibitory concentration of 50% (IC50) doses (determined by MTT) of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan; HCT-8 cells were treated with IC50 doses of irinotecan, cetuximab, and irinotecan plus cetuximab. 18F-FDG incorporation, glucose transport, hexokinase (HK) activity, adenosine triphosphate (ATP) content, annexin V binding, and cell cycle distribution were determined after 24-, 48-, and 72-h treatments. Eight-hour treatments with and without subsequent incubation in drug-free medium were also examined. A clonogenic assay was used to determine the tumor-forming ability of treated cells. RESULTS: Apoptosis was evident in SW620 cells, especially after treatment with irinotecan and 5-FU. 18F-FDG incorporation was increased in SW620 cells after 24- or 48-h treatments with some agents and in HCT-8 cells after irinotecan treatment but was decreased in all 72-h treatments or cell-line combinations including cetuximab. Treatment of SW620 cells for 8 h followed by 64 h in drug-free medium also resulted in decreased 18F-FDG incorporation. Decreased 18F-FDG incorporation broadly corresponded to glucose transport in HCT-8 cells and to HK activity in SW620 cells. Inhibition of glucose transport decreased 18F-FDG incorporation into HCT-8 but not into SW620 cells. ATP levels were decreased by oxaliplatin treatment and increased at 48 or 72 h after irinotecan treatment. CONCLUSION: 18F-FDG incorporation is modulated by therapy-induced changes in both glucose transport and HK activity depending on the tumor cell. Colorectal cells treated with IC50 doses of cetuximab also exhibit decreased 18F-FDG.

Decreased [18F]fluoro-2-deoxy-d-glucose incorporation and increased glucose transport are associated with resistance to 5FU in MCF7 cells in vitro.

INTRODUCTION: Tumor refractoriness to chemotherapy is frequently due to the acquisition of resistance. Resistant cells selected by exposure to chemotherapy agents may exhibit differences in [18F]fluoro-2-deoxy-d-glucose (FDG) incorporation, as compared with sensitive cells. METHODS: FDG incorporation, hexokinase (HK) activity, glucose transport and ATP content were determined in clones of 5-fluorouracil (5FU)-resistant MCF7 cells, established by long-term exposure to increasing 5FU concentrations, and in parental MCF7 cells. RESULTS: FDG incorporation was decreased in MCF7 cells resistant to 5FU; HK activity was similar in the resistant and sensitive cells, while glucose transport was increased, as compared with sensitive cells. Treatment of cells with the glucose efflux inhibitor phloretin increased FDG incorporation to similar levels in the resistant and sensitive cells. Analysis of microarray data demonstrated the expression of GLUT1, 8 and 10 transporters in MCF7 cells. GLUT8 and 10 expression was decreased in the resistant cells, while GLUT1 was only increased in cells resistant to the lowest 5FU concentration. CONCLUSION: FDG incorporation in 5FU-resistant MCF7 cells is decreased, as compared with sensitive cells. Our findings also suggest that this may be due to high rates of membrane glucose transport in the resistant cells resulting in enhanced efflux of FDG. We believe that this is the first demonstration that facilitative glucose transporters can actually decrease the incorporation of FDG.

Tumor 18F-FDG incorporation is enhanced by attenuation of P53 function in breast cancer cells in vitro.

UNLABELLED: Mutations in the p53 gene, often resulting in loss of wild-type (WT) p53 expression, are found at high frequencies in several cancer types. High uptake of (18)F-FDG detected using (18)F-FDG PET has been associated with a poor prognosis. To determine whether high (18)F-FDG uptake may be related to decreased expression of WT p53, we examined (18)F-FDG uptake in cells transfected with dominant negative p53 constructs that abrogate WT p53 function. METHODS: Two clones of MCF-7 breast cancer cells were stably transfected with a dominant negative p53 construct. (18)F-FDG uptake, hexokinase (HK) activity, and glucose transport were measured in each clone and in the control WT cells from which the clones had been derived. The expression of glucose transporters, HKs, and glucose-6-phosphatase was determined using microarray technology. RESULTS: Microarray experiments revealed that glucose transporters 1, 8, and 10 were expressed in MCF-7 cells, whereas glucose-6-phosphatase was absent. HK I was the principal HK in MCF-7 cells but was not differentially expressed at the messenger RNA level in the dominant negative p53 clones, compared with WT cells. However, increased HK activity was observed in both dominant negative p53 clones, compared with WT MCF-7. (18)F-FDG uptake was increased in both clones expressing the dominant negative p53 constructs. CONCLUSION: These data suggest that abrogation of p53 in breast cancer is associated with specific changes in glucose metabolism detected by PET.