F18Fluorouracil

One interesting PET application is the evaluation of tracer kinetics of drugs already used for chemotherapeutic treatment. 5-Fluorouracil (F-18-FU) is the standard cytotoxic agent for the treatment of metastatic colorectal cancer. It has been used

Figure 7 FDG and F-18-FLT in a 66-year-old male patient with a squamous cell carcinoma of the upper lobe of the right lung. (Upper row): Uptake images 60 minutes following tracer application. (Lower row): Parametric images of the tracer influx. Preferentially enhanced FDG uptake in the malignant tumor (left images). F-18-FLT demonstrates the most active, proliferating part of the tumor (right images). Enhanced F-18-FLT uptake in the bone marrow is frequently seen in F-18-FLT studies. (See color insert.)

Figure 7 FDG and F-18-FLT in a 66-year-old male patient with a squamous cell carcinoma of the upper lobe of the right lung. (Upper row): Uptake images 60 minutes following tracer application. (Lower row): Parametric images of the tracer influx. Preferentially enhanced FDG uptake in the malignant tumor (left images). F-18-FLT demonstrates the most active, proliferating part of the tumor (right images). Enhanced F-18-FLT uptake in the bone marrow is frequently seen in F-18-FLT studies. (See color insert.)

in the F-18 labeled form to evaluate the kinetics of the agent using systemic and regional application (32,33). Furthermore, the correlation of tracer retention and therapy result was studied (34). The intravenous application of tracer demonstrated a rapid uptake in normal liver parenchyma, while liver metastases generally showed a low tracer uptake (32). Dimitrakopoulou-Strauss et al. (33) used O-15-water and F-18-FU and compared the systemic and regional application of the tracers in patients with liver metastases from colorectal carcinoma. The authors found that the access to lesions, as measured with O-15-water, was enhanced in 87% of meta-static lesions, which resulted in an improved F-18-FU transport into tumor cells in 83% of the metastases. However, only 33% of the lesions showed an enhanced trapping of F-18-FU two hours after tracer application (Fig. 8). On the basis of data, it can be expected that the retention of 5-FU, which is mandatory for a sufficient treatment result, is limited because of the tracer efflux out of the tumor cells in patients receiving intra-arterial chemotherapy. Enhancement of the treatment effects, therefore, requires a modification of the efflux mechanism.

It is still in discussion as to what resistance mechanisms exist in colorectal tumors. Tseng et al. (35) evaluated the role of Ha-ras overexpression and fluorouracil

Figure 8 PET image in a patient with multiple metastases from a colorectal carcinoma. Image of the F-18-FU uptake two hours after tracer application. Low retention of the tracer is seen in the metastases, which are visible as defects. Therefore the therapeutic success with FU treatment is limited. (See color insert.)

effects. The authors were able to show a close relation between Ha-ras expression and FU sensitivity of the cells. Yoshinare et al. (36) assessed the chemosensitivity to fluor-ouracil in colorectal cancer specimens and found that a high thymidine phosphorylase mRNA expression correlated well with low sensitivity to FU. Furthermore, the authors emphasize that the levels of dihydropyrimidine dehydrogenase (DHPDH), the key enzyme of FU catabolism, and es-nucleoside transporter, an important transmembrane transporter of nucleosides, are possible predictors of sensitivity to FU. Interestingly, we noted a close correlation for HK3 and DHPDH, which may direct to an association of glucose metabolism and FU catabolism (Fig. 9).

It was shown that for other genes such as the multidrug resistance gene (mdr1) one important resistance mechanism is the fast efflux of cytostatic drugs out of the tumor cells, mediated by membrane located, ATP dependent efflux pumps. Guo et al. (37) performed studies in MRP8 overexpressing cells and found that MRP8 reduces the cAMP and CGMP levels and enhances the elimination of cyclic nucleotides from the cells. As a consequence, the MRP8 overexpressing cells were resistant to a range of clinically used nucleotide analogs, including fluorouracil. Interestingly, studies of fluorouracil transport were performed noninvasively with F-18-fluorouracil in patients with liver metastases from colorectal carcinomas to obtain information about the FU transport mechanisms (32). The perfusion of lesions with O-15-water was evaluated, the FU transport was assessed using SUV measurements following a short infusion of F-18-FU together with nonlabeled FU, and the retention was quantified on the basis of the two-hour F-18-FU uptake. Cluster analysis revealed two groups: 43/53 lesions, the majority of the metastases evaluated with O-15-water and F-18-FU, demonstrated a dependency on blood flow, but the retention of F-18-FU two hours after tracer application was low and less than 2.0 SUV. In contrast, 10 metastases had a nonperfusion dependent F-18-FU transport and 7/10

Figure 9 Gene chip analysis revealed a correlation of HK3 and DHPDH, the key enzyme of the FU catabolism.

showed uptake values exceeding 2.0 SUV. The authors conclude that PET with F-18-FU can be used to select those patients showing a higher retention of the tracer in metastatic lesions. With respect to the studies of Tseng et al. (35), the fast efflux of F-18-FU, out of the majority of the metastases, is likely to be due to the enhanced MRP8 expression. Alternatively, different transport pathways for FU must be discussed. F-18-FU is a promising tracer to be used in patients with metastatic color-ectal cancer for the individualization of therapy management.

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