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Cell, Tumor, and Stem Cell Biology |
1 Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; 2 Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; and 3 Section of Medicine, Institute of Cancer Research, Surrey, United Kingdom
Requests for reprints: Eric O. Aboagye, Molecular Therapy Group, Faculty of Medicine, Imperial College London, Clinical Sciences Centre, Medical Research Council Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-3759; Fax: 44-20-8383-2027; E-mail: eric.aboagye{at}imperial.ac.uk.
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Introduction |
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-folate receptor, leading to selective inhibition of tumor thymidylate synthase (6, 10, 11). Quantification of thymidylate synthase inhibition in tumors currently relies on measurement of biochemical changes that accompany thymidylate synthase inhibition (2, 7). For instance, thymidylate synthase inhibition leads to an increase in intracellular pools of the thymidylate synthase substrate dUMP and its corresponding nucleoside 2'-deoxyuridine; thus, pharmacodynamic effects of thymidylate synthase inhibitors have been assessed by measuring elevation of this nucleoside in the patient's plasma (7, 8). However, elevated plasma 2'-deoxyuridine is mainly a marker of global thymidylate synthase inhibition in proliferating cells (i.e., not tumor specific). Positron emission tomography (PET) imaging of thymidylate synthase biochemistry is a strategy that may provide more specific information at the tumor site and could have important use in the development of the next generation of thymidylate synthase inhibitors.
The positron emitting radiotracer 2-[11C]thymidine, a substrate for thymidine kinase 1 (TK1; cytoplasmic thymidine kinase; EC2.7.1.21 ref. 12), a key enzyme in salvage pathway for producing TMP (13), has been assessed for its potential for imaging thymidylate synthase inhibition (14). In that study, patients treated with nolatrexed and scanned 1 hour after drug administration had an increase in tumor 2-[11C]thymidine-related radioactivity levels that correlated with area under the plasma nolatrexed concentration versus time curve (14). It was hypothesized that inhibition of the de novo pathway will lead to enhanced use of TMP produced via the salvage pathway and hence 2-[11C]thymidine uptake. The radiotracer 2-[11C]thymidine is, however, not an ideal PET marker because it is rapidly metabolized in vivo (15). In the present report, we investigated the feasibility of the more metabolically stable thymidine analogue, 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT; ref. 16), to image thymidylate synthase inhibition. We showed for the first time that [18F]FLT-PET can be used very early to image inhibition of thymidylate synthase in vivo by a mechanism involving redistribution of nucleoside transporters to the plasma membrane.
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Materials and Methods |
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Cell lines and tumors. Radiation-induced fibrosarcoma-1 (RIF-1) cells (18) were cultured in RPMI 1640 (Life Technologies, Strathclyde, United Kingdom) supplemented with 10% fetal bovine serum (Sigma, Poole, United Kingdom) and antibiotics in a 5% CO2 incubator at 37°C. Exponentially growing cells were used for the in vitro radiotracer studies or inoculated into 6- to 8-week-old-male C3H/Hej mice obtained from Harlan UK Ltd. (Bicester, United Kingdom). Tumors were induced by inoculation of 5 x 105 cells s.c. on the back of the mice. All animal work was done by licensed investigators in accordance with the United Kingdom's "Guidance on the Operation of Animals (Scientific Procedures) Act 1986" (HMSO, London, United Kingdom, 1990) and in full compliance with government regulations and guidelines on the welfare of animals in experimental neoplasia (19). Tumors were selected for PET imaging studies when they reached 5 to 8 mm in diameter.
PET scanning and image analysis. Mice were scanned on a dedicated small animal PET scanner (quad-HIDAC; Oxford Positron Systems, Weston-on-the-Green, United Kingdom; refs. 18, 20, 21). Before scanning, the mice were treated with either PBS (control) or 5-FU at a single i.p. dose of 165 mg/kg body weight and scanned at 1 to 2 hours after drug injection. For scanning, anesthesia was induced with isofluorane/O2/N2O and the tail veins of the mice were cannulated. The animals were placed within a thermostatically controlled bed and positioned prone within the scanner. The bed was calibrated to provide a mouse rectal temperature of 
37°C. A bolus injection of [18F]FLT (2.96-3.7 MBq; 80-100 µCi) was given i.v. via the tail vein cannula and scanning commenced. Dynamic emission scans were acquired in list-mode format over 60 minutes. The acquired data were then sorted into 0.5-mm sinogram bins and 19 time frames (0.5 x 0.5 x 0.5 mm voxels; 4 x 15, 4 x 60, and 11 x 300 seconds) for image reconstruction, which was done by filtered back projection using a two-dimensional Hamming filter (cutoff 0.6). The image data-sets obtained were transferred to a SUN workstation (Ultra 10; SUN Microsystems, Santa Clara, CA) and visualized using the Analyze software (version 6.0; Biomedical Imaging Resource, Mayo Clinic, Rochester, MN). Cumulative images of the dynamic data composed of 0 to 1 minute after injection and 30 to 60 minutes after injection were used for visualization of radiotracer uptake and to define the regions of interest (ROI) on heart (mainly blood pool) and tumors, respectively. ROIs were defined on five tumor and five heart slices (each 0.5 mm thickness). The count densities were averaged for each ROI at each of the 19 time points to obtain a time versus radioactivity curve (TAC) for the ROIs. Tumor TAC was normalized to that of heart at each of the time points to obtain the normalized uptake value (NUV). The [18F]FLT-PET data from heart were used as internal input function for normalizing tumor data because it comprises mainly of blood radioactivity (18). The NUV at 60 minutes after injection (NUV60), the area under the NUV curve (AUC) calculated as the integral of NUV from 0 to 60 minutes, and the fractional retention of tracer (FRT), the radioactivity at 60 minutes relative to that at 2.5 minutes, were used for comparisons. FRT is a useful variable in that it indicates the proportion of radiotracer delivered to the tumor that is retained. It therefore normalizes tumor [18F]FLT uptake to delivery.
Analysis of tumor 2'-deoxyuridine levels. To confirm that thymidylate synthase was inhibited by 5-FU, 2'-deoxyuridine levels were assessed by high-performance liquid chromatography (HPLC). Plasma and RIF-1 tumors were taken from mice treated with PBS or 165 mg/kg 5-FU at 2 hours after injection and immediately snap frozen in liquid nitrogen. This time point was selected to coincide with the imaging assay. Plasma samples (150 µL) were initially prepared using perchlorate protein precipitation; after neutralization and centrifugation, the supernatant was purified by solid-phase extraction. Whole (weighed) tumor samples were homogenized and the homogenate was treated similar to plasma samples. After evaporation to dryness using a vacuum centrifuge, the samples were reconstituted for analysis by reverse-phase HPLC as described previously (22). 2'-Deoxyuridine was separated on a C18 stationary phase with a mobile phase comprising 0.1% trifluoroacetic acid and detected at 267 nm using a UV photodiode array detector. 2'-Deoxyuridine losses from sample preparation were estimated by measuring the recovered activity of [5-3H]2'-deoxyuridine spiked into blank plasma or tumor samples. Chromatographic peak areas for the samples were compared with a calibration curve; data were expressed as micromole per liter and nanomole per gram for plasma and tumors, respectively.
Analysis of tumor TK1 protein and cofactor levels. TK1 protein and cofactor (ATP) were assessed by Western blot and bioluminescence assays, respectively. RIF-1 tumors were excised from mice treated with PBS or 165 mg/kg 5-FU at 2 hours after injection and snap frozen in liquid nitrogen. Tumors were pulverized in liquid nitrogen and homogenized in ice-cold PBS using an Ultra-Turrax homogenizer (IKA, Staufen, Germany). The samples were then centrifuged at 800 x g (for 30 minutes at 4°C) and supernatants were analyzed for protein content using a commercial bicinchoninic acid (BCA) protein assay kit (Perbio Science, Cheshire, United Kingdom). Aliquots of the supernatants (containing 30 µg protein) were mixed with equivalent volumes of native Tris-glycine sample buffer (Invitrogen Life Science, Paisley, United Kingdom) and separated on a precast Tris-glycine (4-20%) gel (Invitrogen). Western blot analysis was done as described previously (18, 20). For quantification of band intensities, the films were scanned using a GS-710 Calibrated Imaging Densitometer (Bio-Rad Laboratories, Hertfordshire, United Kingdom) and analyzed with the Quantity One software (version 4.0.3; Bio-Rad Laboratories). ATP levels were determined by a bioluminescence assay as described previously (18, 20) using the same supernatants used for the Western blots above. A calibration curve was prepared from ATP standards, which were provided with the ATP assay kit.
Incorporation of radioactivity into DNA. RIF-1 cells were cultured in full growth medium as above and treated with 1 or 10 µg/mL 5-FU dissolved in PBS or an equal volume of PBS for 2 hours. After drug treatment, the cells were washed and incubated with 0.185 MBq tritiated thymidine ([3H]TdR) or [3H]FLT for 1 hour. The cells were washed and scraped into plastic tubes. The cellular protein content of whole cells was assayed by a commercial BCA protein assay kit and used for normalization of radioactivity levels in DNA (assuming no losses in the DNA assay) on different days. The cells were centrifuged. DNA was isolated from whole-cell pellet using the AquaPure Genomic Isolation kit (Bio-Rad Laboratories, Hercules, CA). Hydrated DNA samples were placed in opaque 24-well plates (Perkin-Elmer, Beaconsfield, United Kingdom) and left to dry. Aliquots (500 µL) of scintillant (Microscint-40; Perkin-Elmer) were added to each well and the radioactivity in each well was counted on a ß-counter (TopCount NXT, Packard Instruments, Meriden, CT). Data were quench corrected and expressed as counts per minute (cpm)/mg protein.
Cellular membrane transport inhibition assays. To determine the mechanism of whole-cell plasma membrane transport, cell uptake studies were done with [18F]FLT in the presence or absence of various known inhibitors (23). RIF-1 cells were cultured as above and treated with full growth medium containing PBS or 10 µg/mL of 5-FU for 2 hours. After drug treatment, the cells were washed and trypsinized. The effect of trypsin was blocked with full growth medium. The cells were washed again and suspended in HBSS (Sigma). Cells (2 x 106) were preincubated for 15 minutes in HBSS buffer containing PBS (control) or an inhibitor of nucleoside or nucleobase transport (and phosphorylation), including 20 µmol/L nitrobenzylthioguanosine (NBTG), 20 µmol/L dipyridamole, 2 mmol/L thymidine, 2 mmol/L uridine, 2 mmol/L adenine, and 2 mmol/L thymine; total incubation volume of 1 mL. The cells were then incubated with 1.8 to 3.7 MBq [18F]FLT at room temperature (20°C) for 1 hour with mild shaking. At the end of the incubation period, the reaction was quickly stopped by adding 5 mL ice-cold PBS and centrifuged at 500 x g for 5 minutes. The supernatant was removed; the cells were washed once and resuspended in 100 µL of 2.5x lysis buffer (10% sodium carbonate, 0.5% sodium dodecyl sulphate, 0.5mol/L sodium hydroxide) until the cells were fully disintegrated. The solution was carefully transferred into opaque 24-well plates and air dried. Aliquots (500 µL) of scintillant were added and the radioactivity was counted using a microplate ß-counter (TopCount). Data were expressed as a percentage of the radioactivity added (percent cpm of dose solution per 2 x 106 cells). For comparison, the uptake of [3H]TdR in 10 µg/mL 5-FU-treated cells was determined as for [18F]FLT above in the presence and absence of NBTG and expressed as a percentage of the mean uptake in uninhibited cells.
To confirm or rule out the involvement of nucleobase transport, transport studies in PBS-treated cells or 10 µg/mL 5-FU-treated cells were done as above for [18F]FLT but with 0.185 MBq [3H]adenine as radiotracer. In these studies, 2 mmol/L thymidine was used to saturate phosphorylation of adenine.
Kinetics of nucleoside transport. In these studies, exponentially growing RIF-1 cells were treated for 2 hours with PBS or 5-FU at concentrations of 1 or 10 µg/mL. Single cells prepared by trypsinization were suspended in HBSS with mild shaking. To assess plasma membrane NBMPR-sensitive nucleoside transporter-binding sites on RIF-1 cells, 2 x 106 cells were incubated with 0.1, 0.25, 0.5, 1, 2, 4, 8, 16 nmol/L [3H]NBMPR in HBSS. The total incubation volume was 400 µL and the studies were carried out at room temperature (20°C) for 60 minutes (equilibrium binding). In parallel experiments to assess nonspecific binding, equal numbers of cells were preincubated with 20 µmol/L of the specific inhibitor, NBTG, for 15 minutes and then incubated with [3H]NBMPR at the same concentration range. At the end of the incubation, the reaction was quickly stopped by adding 5 mL ice-cold Na+ buffer [150 mmol/L NaCl, 5 mmol/L Tris-HCl (pH 7.4)] and the mixture was centrifuged at 500 x g for 5 minutes. The supernatant was removed and the cells were washed once and resuspended in 100 µL lysis buffer until they were fully disintegrated. The solution was carefully transferred into opaque 24-well plates and air dried, and the radioactivity was counted (TopCount). Specific binding (binding sites per cell) was defined as the difference in [3H]NBMPR content in the presence and absence of NBTG. The maximal binding (Bmax; the number of transporters) and the concentration of ligand required to reach half-maximal binding (KD; affinity) were determined by curve fitting using the Prism software, version 4.03 (GraphPad, San Diego, CA). Data were fitted to the equation: Y = Bmax x X / (KD + X), where Y and X are the specific binding and [3H]NBMPR concentration in nmol/L, respectively.
Statistics. Statistical analyses were done using the Prism software, version 4.03 (GraphPad). Differences between PBS- and 5-FU-treated groups were tested for significance using the Student's t test for unpaired data. Two-tailed Ps 
0.05 were considered significant.
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15 minutes. A summary of the kinetic components calculated from the TACs are depicted in Table 1
. All variables, including the NUV60, FRT, and AUC, were significantly higher in the 5-FU-treated mice compared with vehicle controls (Table 1). We also examine whether thymidylate synthase was inhibited under the conditions used. Both plasma and tumor 2'-deoxyuridine levels, surrogate measures of thymidylate synthase inhibition (7, 8), were significantly increased after 5-FU treatment by 2-fold (Table 1).
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0.03; Fig. 2C). The amount of radioactivity in DNA was 26.5% of that in whole cells. In contrast, there was no change in [3H]FLT uptake into DNA (Fig. 2D); the amount of radioactivity in DNA was 0.2% of that in whole cells. This indicates that thymidylate synthase inhibition does not increase [18F]FLT uptake into the DNA pool.
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Discussion |
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[18F]FLT has superior in vivo stability compared with 2-[11C]thymidine and [124I]iododeoxyuridine (29). Hence, we assessed the feasibility of using this radiotracer for imaging thymidylate synthase inhibition. Marked increase in [18F]FLT-PET imaging end points together with marked increases in both plasma and tumor 2'-deoxyuridine were seen 1 to 2 hours after 5-FU treatment in vivo. We have proposed in previous studies that the mechanism of increased radiolabeled thymidine uptake following thymidylate synthase inhibition may involve increased use of the salvage pathway for producing DNA in an attempt of cells to overcome the block in TMP production via the de novo pathway (14, 24). This assertion was based on the use of radiolabeled thymidine, which is readily incorporated into DNA. In the present study, we showed that [3H]TdR incorporation into DNA was enhanced by 5-FU treatment and that the DNA component comprised a substantial part of whole-cell uptake (26.5%). The proportion of [3H]FLT in DNA was only 0.2% that of whole cell and did not change after 5-FU treatment. This finding indicated that the mechanisms of retention of the two radiotracers were different. It also indicated that enhanced incorporation of thymidine analogues into DNA to overcome the block of the de novo pathway per se was not responsible for the general increase in nucleoside uptake. Examination of TK1 and ATP levels, the enzyme system responsible for the initial commitment of thymidine into the salvage pathway, showed no change in levels that could account for the increase in [18F]FLT uptake early after 5-FU treatment. Lastly, we examined membrane transport of [18F]FLT and showed that [18F]FLT was transported by ENT1, albeit at low levels compared with [3H]TdR. The low substrate specificity of [18F]FLT for ENT1 even under conditions of 5-FU induction may be due to the lack of a 3'-OH group, which seems to be important for the transport of nucleoside analogues by ENT1 (30, 31).
Interestingly, we discovered that treatment of RIF-1 cells with 10 µg/mL 5-FU increased plasma membrane NBMPR-sensitive nucleoside transporter (predominantly ENT1) binding sites from 49,101 in untreated cells to 73,142 (P = 0.03). Thus, although a poor substrate, [18F]FLT is transported by ENT1 under conditions of thymidylate synthase inhibition due to the large increase in numbers of plasma membrane ENT1 transporters. The lack of a change in transporter KD (P 
0.41) with 5-FU treatment indicates that there was no modification in affinity of the transporter and/or no recruitment of other ENT transporter subtypes. Total 100,000 x g membrane fractions prepared from PBS- and 5-FU-treated RIF-1 tumors did not show differences in [3H]NBMPR binding; ENT1 mRNA levels of control and 10 µg/mL 5-FU-treated RIF-1 cells measured by quantitative real-time PCR were not different from each other.4 These findings indicate that increased salvage kinetics induced by thymidylate synthase inhibition is not due to increased transcription or translation of ENT1 but is largely or exclusively due to redistribution of the transporter from the intracellular compartment of cells to the plasma membrane. ENT1 is predominantly localized on the plasma membrane of both human and mouse cells (32, 33). In addition to the plasma membrane, ENT1 is known to localize to mitochondria (30). Whether it is the mitochondrial pool that redistributes to the membrane remains to be determined. It is unlikely that a third ENT family member, ENT3, which is insensitive to NBMPR and has been shown to localize in the intracellular/lysosomal pool (33), will be responsible for the observed effects. Furthermore, the reason why thymidylate synthase inhibitors (11, 14, 24, 34), but not other anticancer agents, affect radiolabeled nucleoside uptake through ENT1 in this manner remains to be elucidated.
In general, the [18F]FLT-PET methodology should allow early pharmacodynamic effects of thymidylate synthase inhibitors to be studied in preclinical models and in patients. Such studies will involve a baseline [18F]FLT-PET scan followed by another [18F]FLT-PET scan soon after drug treatment. The time course of [18F]FLT-PET changes will depend on the pharmacokinetics of the thymidylate synthase inhibitor, dose, and mechanism of interaction of the inhibitor with thymidylate synthase (i.e., rate and persistence of thymidylate synthase inhibition). A limitation of the technology is the relatively short length of time that PET measurements will continue to show increased [18F]FLT uptake, reflecting inhibition of thymidylate synthase inhibition, rather than a decrease in [18F]FLT uptake, reflecting inhibition of cell proliferation. Our previous studies with 5-FU and AG337 indicate that this time window is 6 and 24 hours in cultured cells (24). In vivo studies at the same dose of 5-FU used here shows a reduction in [18F]FLT uptake at 24 and 48 hours (18). Mathematical modeling to calculate [18F]FLT permeability product surface area may allow the thymidylate synthase inhibition effect, which relates to nucleoside transport to be measured at 24 hours or longer. In the use of [18F]FLT-PET for monitoring the antiproliferative activity of thymidylate synthase inhibitors, as opposed to its use for determining thymidylate synthase inhibitory activity reported here, the early increases might be interpreted as a "flare" effect and confound the [18F]FLT-PET studies. We will caution the use of [18F]FLT-PET for monitoring antiproliferative activity of 5-FU-containing regimen during the dosing period (soon after a bolus dose or during and soon after continuous infusion); the same applies to chronic dosing with other thymidylate synthase inhibitors. We will speculate from our previous in vitro and in vivo studies (18, 24) that [18F]FLT-PET-based antiproliferation measurements could be done a few days after 5-FU administration.
Imaging methods could accelerate drug development by providing information on whether adequate levels of drug are achieved, whether the drug hits its intended target, and whether the expected biological activity is achieved (35). [18F]FLT-PET could be used to determine if thymidylate synthase inhibitors modulate their intended molecular target in tumors and normal tissues. In summary, [18F]FLT-PET imaging can be used to measure thymidylate synthase inhibition in tumors in vivo very early after drug administration. The cellular mechanism by which [18F]FLT-PET measures thymidylate synthase involves redistribution of nucleoside transporters to the plasma membrane.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank the Wellcome Trust for award of the Joint Infrastructure fund that enabled us to purchase the HIDAC PET scanner.
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Footnotes |
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Received 3/13/06. Revised 6/ 2/06. Accepted 6/15/06.
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-folate receptor-overexpressing tumors. Cancer Res 2005;65:11721–8.This article has been cited by other articles:
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) and 5-FU-treated (
) RIF-1 tumors. Tumor-bearing mice were treated with PBS or 5-FU at a dose of 165 mg/kg i.p. and scanned at 1 to 2 hours after injection. For each mouse, tumor/heart radioactivity ratios from five slices were averaged at each of the 19 time points. Points, mean tumor/heart ratios from eight control mice and five 5-FU-treated mice; bars, SE.
