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Cancer Research Campaign Biomedical Magnetic Resonance Research Unit, Department of Biochemistry and Immunology, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom [P. M. J. M., J. R. G.], and Cancer Research Campaign Clinical Magnetic Resonance Research Group [P. M. J. M., M. O. L.] and Cancer Research Campaign Centre for Cancer Therapeutics [P. M. J. M., I. R. J.], Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey SM2, United Kingdom
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ABSTRACT |
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15% of the total detectable 19F signal) consisted of
the epimer 
-fluorodeoxymannose (FDM) and various conjugates. Mice
treated with 5-fluorouracil (130 mg/kg) received, 48 h later, a
repeat dose of FDG. The change in the rate of FDM formation, but not
the FDG or total 19F signal, correlated significantly with
the response to 5-fluorouracil (P = 0.032), suggesting that 19F MRS of FDM metabolism in
vivo may be a novel means of predicting tumor response. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, which can persist in tissues for up to 48 h (3)
. If
19F MRS could measure the rate of FDG-6P
metabolism or a surrogate of FDG-6P in solid tumors in vivo,
then a useful clinical tool might be available. In this study, we aimed
to determine whether 19F MRS could detect
metabolism of FDG beyond FDG-6P in solid murine tumors in
vivo and whether FDG uptake (total 19F
signal) or formation of FDM metabolites correlated with tumor response
to chemotherapy.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Tumors and Experimental Set-Up in Vivo.
Murine RIFs (RIF-1) were grown in C3H mice, and tumor volume was
calculated as described previously (7)
. Anesthetized
animals were placed in the bore of a Varian 200/330 4.7T spectrometer
with tumors (0.4–1 g) hung into a dual-tuned
1H/19F surface coil (12-mm
diameter) with a reference bulb containing 10 µl of 5FU (2 µmol).
FDG was injected i.p. as a 0.2-ml bolus (1.4 mmol/kg), and nonlocalized
19F spectra were acquired immediately in 10-min
blocks for 120 min (12 x 1500 transients of 0.4 s)
using a spectral width of 20 KHz with a 45° pulse at the coil center.
Seven mice received a single dose of 5FU (1 mmol/kg, i.p.) 3 h
after the initial FDG injection, This dose of 5FU is known to cause
significant shrinkage of RIF-1 tumors within 48 h, with maximum
decreases observed at 3–5 days, followed by a return to pretreatment
size after 
10 days (7)
. After 48 h, the
19F MRS experiment was repeated using a second
dose of FDG. The response to 5FU was assessed by measuring tumors every
2 or 3 days for at least 7 days and recording: (a) the MXD;
and (b) the TV7.
Extracts and Analyses in Vitro.
Some RIF-1 tumors were not treated with 5FU but instead were
freeze-clamped 2 h after FDG treatment for
19F MRS analysis in vitro at 4.7 T, or
in some cases using a vertical high-resolution 8.5T Bruker system.
Perchlorate extracts were made as described previously
(8)
, and 5FU was added to a final concentration of 2
mM to act as an internal standard for
quantitation. Perchlorate extracts were also made from: (a)
plasma samples of 0.25 ml obtained from mice 30 min after injection of
FDG; and (b) cultured RIF-1 cells. Confluent RIF-1 cell
cultures were incubated for 4 h with or without 200
µM 6AN prior to the addition of 1.5
mM FDG. After 2 h, the medium was removed,
the cell monolayer was washed with PBS, and the cells were detached by
using a 0.01 M EDTA-trypsin mix. The cells were
briefly centrifuged, and the pellet was extracted (8)
.
Quantitative analysis of tumor or cell extracts by
19F MRS was performed at 4.7 T on 1-ml samples
using a spectral width of 20 KHz, a 90° pulse, and 4000 x 14.5-s transients. Spectra received 20 Hz line broadening, and
peak integrals were measured by FITSPEC, as described previously
(7)
. This method provided a sensitivity limit of 10 nmol.
Extracts of isolated cells were scanned for at least 10,000 transients.
19F MRS at high resolution was performed at 8.5 T
on 1-ml samples using a spectral width of 24 KHz, a 22° pulse, and
10,000 x 6-s transients. Spectra received 2 Hz line
broadening.
Enzyme Analyses.
Confluent cultures of RIF-1 cells were trypsinized, centrifuged, and
resuspended in 1 ml (>107 cells/ml), before the
addition of Triton X-100 to a final concentration of 1%. The cell
suspension was then frozen at -20°C and used for enzyme analysis
within 24 h. Prior to enzymatic analysis, cell suspensions were
freeze-thawed once more and maintained at 4°C. HK and PGI activity
were assayed spectrophotometrically at 25°C by recording the
absorbance of NADP at 340 nm, according to the methods described by
Bergmeyer (9)
. The assay efficiency was tested by testing
dilutions of the pure enzymes to check that 1 unit of enzyme activity
produced 1 µmol substrate per minute. Results were expressed as
milliunits/mg cell protein from duplicate samples.
Data Analysis.
All 19F data were analyzed as described
previously to calculate the peak integrals and chemical shifts
(7)
. Under the conditions used in vivo, FDG and
metabolites were 32% saturated, and the 5FU external standard was 74%
saturated; appropriate corrections allowed estimation of drug
concentrations in the tumor. Graphical representation of the data (peak
integral versus time) allowed calculation of the AUC for the
FDG and FDM groups and total 19F, as µmoles
formed in 2 h per g tumor, and linear regression was used to
calculate the rate of total (- plus ß-) FDM formation as
nmol/min/g tumor. The strength of the relationship between parameters
was measured using linear regression to obtain the correlation
coefficient r and the associated P for
significance (<0.05).
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Results |
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- and ß-anomers of FDG were readily resolved from one
another in the stock solution; the two peaks showed a chemical shift
(
F) difference of 0.25 ppm when 10 Hz line
broadening was used. T1s of 1.74 ± 0.03 and 1.85 ± 0.03 s, respectively, were
measured, comparable with values measured in cells by Kojima et
al. (4)
, who reported that FDG and FDM and their
conjugates all had similar T1s. Increasing the
number of transients to 6400 x 9 s allowed
detection of an additional peak at -6.0 ppm (upfield), consistent with
the presence of a small amount of FDM (0.13 µmol/ml). This low level
of FDM contamination (0.09%) in the stock solution would be
undetectable in vivo; therefore, any FDM detected in
vivo would have to be attributable to FDG metabolism.
19F MRS of FDG in RIF-1 Tumors in Vivo.
The FDG signal (0 ppm) appeared at -31 ppm (upfield) from the 5FU
reference within 2 min after administration. In 2 of 13 tumors, the
maximum signal intensity (Cmax) of this group
(-FDG ± 6P plus ß-FDG ± 6P)
developed within 10 min; in the other 11 tumors, it was after 30 min
(Fig. 2)
. The T1 of the FDG group measured in three
different tumors in vivo was 1.35 ± 0.03 s (mean ± SE) at 30–60 min after injection.
In all tumors studied, the major FDM group (-FDM±P) was detectable
after 10 min at -5.3 ppm from the FDG group, and sometimes, the minor
FDM group (ß-FDM±P) was detectable after 60 min further upfield at
-23.8 ppm. The mean Cmax of the FDG group was 1.8 ± 0.2 mM at 60 min after injection, whereas
the FDM group increased linearly up to 110 min, allowing calculation of
a rate of formation of 2.3 ± 0.5 nmol/min/g
(mean ± SE; n = 10). Unlike
in brain tissue (3
, 5
, 6)
, metabolites of the PPP
(approximately +3 ppm downfield from FDG) were not detectable. In some
cases, a small peak corresponding to UDP-FDG could be detected at
approximately -2 ppm (Fig. 2b)
. In a separate cohort of
three mice, the plasma concentration was determined to be 1.6 ± 0.2 mM (mean ± SE) 30 min
after injection, similar to the concentration calculated for tumor FDG
in vivo.
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. These peaks have been described in mouse brain (6)
,
allowing the assignments described in Fig. 3
and below. On the basis of
these previous assignments, the major group of peaks (fig. 3a)
are the ß- and -anomers of FDG-6P and FDG-1P,
whereas the doublet on Fig. 3b
would be the ß- and
-anomers of UDP-FDG. The next group of peaks upfield at Fig. 3, c and d
, is the -FDM group, beginning with
FDM-1,6-P2 and FDM-1P (Fig. 3c)
,
followed by FDM-6P, FDM, and the most upfield peak in this group,
UDP-FDM (Fig. 3d)
. Fig. 3e
is the ß-FDM±P
group. Peak integration showed that the combined FDM groups (Fig. 3, c–e)
were 18–20% of the total 19F
signal detectable, demonstrating that considerable metabolism had
occurred beyond FDG-6P at 2 h after injection.
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-FDM±P and 204 nmol FDG±P after 2 h incubation with 1.5 mM FDG. ß-FDM±P was not detectable
in these cell extracts. Assuming a cell volume of 40
µl/107 cells (10)
, this would be
equivalent to 0.38 mM FDM±P, similar to the concentrations
formed in vivo after 2 h. Assuming approximately
2 x 108 RIF-1 cells/g tumor
tissue and linear rates of FDM formation, this would correspond to a
formation rate of 2.6 nmol/min/g, similar to the rate determined
in vivo (see above). Higher FDG concentrations (15
mM) led to formation of 1
mM FDM±P in 2 h. - or ß-FDM±P was not
detectable in cultures incubated for 1 min with FDG or in cultures
preincubated with 6AN prior to FDG. Low levels of FDG±P and UDP-FDG,
80 and 12 nmol, respectively, were however detectable in extracts
obtained from cells incubated with 6AN.
Enzyme Activity of HK and PGI.
The mean activity of HK was 43 ± 12 millunits/mg, which
in each of four preparations was always exceeded by PGI, giving a mean
activity of 2000 ± 250 milliunits/mg (mean ± SE). The mean ratio of PGI/HK activity was 64 ± 26.
Effect of 5FU Treatment on FDG Metabolism in Vivo.
The total 19F signal or FDG AUC showed very
little change after 5FU treatment; the ratios before and after
treatment were 1.04 ± 0.14 for FDG and 1.06 ± 0.14 for total 19F (mean ± SE; n = 7). In contrast, the rate of
formation of new FDM showed large decreases of up to 5-fold. In five of
seven cases, low levels of FDM (30–90 nmol) could still be detected
48 h after the first FDG treatment, and in two of seven cases, the
FDG group was detectable (38 and 43 nmol). This is consistent with the
observations of Kanazawa et al. (3
, 6)
, who
reported that UDP-FDM persisted for at least 48 h in heart,
muscle, and particularly ascites tumor cells. Where detectable (five of
seven), the mean FDM concentration was 0.077 ± 0.023
mM (±SE), 30% of the maximum amount
eventually formed after the second injection of FDG.
Correlation between Tumor Response and FDG Metabolism Before and
After 5FU Treatment.
All RIF-1 tumors treated with 5FU responded by a decrease in volume
that was clearly visible after 48 h. However, the extent of the
response expressed either as the MXD or TV7 was variable. The MXD
correlated strongly with TV7 (r = 0.85;
P = 0.017), which suggested that both
measurements were valid assessments of 5FU cytotoxicity.
Fig. 4, a and b
, shows that prior to 5FU treatment, the
four 19F MRS parameters of total
19F signal, FDG, FDM AUC, and FDM rate correlated
positively with tumor response expressed as TV7, but this was only
significant for the FDM AUC, r = 0.81
(P = 0.028; Fig. 4b
). A similar
pattern was seen if tumor response was expressed using MXD, although in
all cases the correlation was weaker and did not reach significance for
FDM. After 5FU treatment (Fig. 4, c and d)
, the
change in AUC for FDG or 19F signal showed no
correlation with response but was stronger for FDM AUC and significant
for the FDM rate when response was expressed as MXD,
r = 0.80 (P = 0.032; Fig. 4d
). When the four parameters were correlated
with TV7, the same pattern was observed of FDM correlating most
strongly with response: r = 0.29, 0.21, 0.34,
and 0.63 for the AUCs of 19F, FDG, FDM, and FDM
rate, respectively.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-FDM
and its conjugates, correlated with tumor response to 5FU treatment,
whereas total 19F signal or FDG and its
conjugates did not correlate significantly. These observations
demonstrate that FDG can undergo considerable metabolism in solid
tumors and suggests that methods that only detect total label,
e.g., 18FDG, would be less likely to
predict tumor response.
Glucose Utilization by Tumors.
The high glycolytic rates exhibited by solid tumors permit their
detection in situ, because trace levels of radioactive FDG,
18FDG, can be measured by the highly sensitive
technique of PET (2)
. FDG enters the cells via the
facilitative glucose carrier, is phosphorylated by a HK to FDG-6P, but
then unlike glucose, is believed to undergo little further metabolism,
so that 18FDG becomes trapped (2)
.
It is assumed that for a tumor to accumulate glucose, it must be
viable, and thus a change in glucose accumulation would reflect a
change in tumor viability or metabolic activity. This hypothesis is the
rationale for the application of PET to detect changes in tumor glucose
utilization soon after treatment, as an early predictor of tumor
response. However, the approach has not always been successful, perhaps
because of the variety of biochemical responses that can occur after
therapy. For example, tumor blood flow may increase or decrease, and
the immune response may also be unpredictable (2
, 11)
. In
addition, the method detects total label and relies upon a
three-compartment model to obtain rates of glucose uptake and
phosphorylation or dephosphorylation. In principle, a method that can
distinguish the metabolites of FDG would improve modeling of glucose
utilization.
19F MRS of FDG.
The first reported demonstration by 19F MRS that
FDG is metabolized beyond FDG-6P was in rat brain in vivo
(12)
, and this was repeated in mouse ascites
(4)
, heart, muscle, and liver (6)
, all
ex vivo. Although the first metabolite of FDG, FDG-6P,
cannot be resolved from FDG in vivo, the primary metabolites
of the PPP (Fig. 1)
could be detected in brain, heart, and particularly
liver, 3 ppm downfield from FDG (6
, 12)
. In extracts of
mouse ascites, these PPP metabolites were identified only at very low
levels (3)
. In contrast, the major metabolite in all
organs, except liver, appeared to be -FDM±P, leading eventually to
UDP-FDM (Fig. 1)
. UDP-FDM persists for 12–48 h at near
mM concentrations in ascites cells, and this
permitted fluoroimaging in vivo (3)
. Formation
of FDM-6P is likely to occur through epimerization of FDG-6P via the
enzyme PGI, although this is not proven (5)
. PGI is widely
distributed in the cytoplasmic compartment of the cell, measurable
amounts exist in the serum, and erythrocytes, liver, muscle, bone,
brain, and lung are rich in PGI (9)
. In fact, plasma
levels of PGI are raised in metastatic cancer and can be used as an
index of tumor growth or activity in the body (13)
.
It is conceivable that FDM is formed through isomerization of FDG, via
GI in the tumor cell, plasma, or a major organ, followed by conversion
to FDM-6P via HK and then to FDG±6P and UDP conjugates of FDM and FDG
in the tumor (Fig. 1)
. In this case, inhibition of PGI would not
prevent formation of FDM phosphates and UDP-FDM. The second metabolite
in the PPP, 6PG, is a strong inhibitor of PGI, and high levels of 6PG
are thought to be responsible for inhibition of glycolysis in RIF-1
cells after incubation of the cells with 6AN (Fig. 1
; Ref.
14
). We found that 6AN blocked formation of
19F MRS detectable FDM±P but not formation of
UDP-FDG, suggesting that at least in tumor cells, the major source of
FDM formation is through the action of the enzyme PGI. Furthermore, FDM
was not detectable in plasma, and the rate of formation of FDM in
isolated RIF-1 cells was similar to that measured in vivo.
All of which suggests that the FDM±P detected in tumors in
vivo probably results entirely from conversion of FDG-6P to FDM-6P
by PGI and not from FDM circulating in the plasma after FDG metabolism
by other tissues. The rate of FDM formation occurs at 1% of the
rate of glucose consumption reported in rat breast xenograft tumors
(15)
, presumably because the epimerization by PGI is
relatively inefficient. For FDM formation to be a surrogate for HK
activity, PGI activity would have to greatly exceed HK activity, and
indeed we observed a relative ratio of 64:1. In contrast, brain, heart,
and erythrocytes have relative ratios of 5, 9, and 17, respectively,
but skeletal muscle, a tissue that has the capacity for high glycolytic
rates, has a ratio of 117 (16)
. RIF-1 tumors are known to
be very glycolytic (17)
, and thus the high PGI/HK may be
indicative of strongly glycolytic cells.
Correlation of FDG Metabolism with Tumor Response.
There was a significant correlation between the change in rate of FDM
formation and response, a weaker correlation between the FDM AUC and
response, and no correlation with FDG or total
19F signal. Thus, 2 days after treatment, only
the FDM signal could be used to predict the extent of tumor response to
treatment. The calculation was, however, complicated by the presence in
most cases of residual FDM (presumably mostly UDP-FDM) from the first
FDG dose. This amount had to be measured first, so that the true amount
of new FDM could be determined, otherwise the FDM would have
been overestimated. It is also conceivable that these residual FDM
metabolites could inhibit the activity of the enzymes PGI, PGM, and
glucose-1-phosphate uridyltransferase and thus lead to underestimation
of the amount of FDG-6P that was formed. Most of the 5FU administered
would be metabolized to fluoro-uridine phosphates, including
FUDP-glucose (8)
, and this might interfere with FDG
metabolism in an unpredictable manner. Nevertheless, overall the
results indicated that the tumors showing the largest change in tumor
volume had a decrease in the rate of FDM formation (five of seven; Fig. 4d
), implying a decrease in the rate of glucose
phosphorylation and thus glycolysis. This is consistent with the report
of Aboagye et al. (18)
, who showed that a
similar dose of 5FU (160 mg/kg i.p.) induced a mean decrease in total
lactate formation by RIF-1 tumors of 50–70%, 24–48 h after
treatment. Thus, the response of RIF-1 tumors to 5FU probably involves
a decrease in the rate of glycolysis, and this may be detected by
19F MRS as a decrease in the rate of formation of
FDM from FDG. In the model of Aboagye et al.
(18)
, it was concluded that the decrease in tumor volume
occurred through apoptotic cell death, and therefore, changes in tumor
viability were attributable to changes in cell viability rather than
changes in tumor blood flow.
Considering the potential complications of residual FDM and the effects
of 5FU on FDG metabolism, it is also important that positive
correlations were found between 19F levels and
tumor response prior to 5FU treatment (Fig. 4, a and b)
. This was strongest for FDM and was significant for the
FDM AUC (r = 0.81; P = 0.03). Removal of glucose from the plasma and lactate formation
have been found to be highly variable in rat xenograft models but were
shown to be proportional to tumor blood flow and inversely proportional
to tumor wet weight (15)
. In a hormone-responsive rat
tumor model, deoxyglucose uptake postovariectomy correlated with the
number of S-phase cells and tumor blood flow, but more strongly with
the latter (11)
. These articles suggest that high glucose
utilization may reflect both the ease with which a drug enters the
tumor space as well as the number of cycling cells, important
parameters determining tumor drug sensitivity. For 5FU sensitivity, FDG
may reflect tumor blood flow, but metabolism to FDM may be a better
indicator of cell viability.
Toxicity.
About 30 years ago, experiments with deoxyfluoropyranoses focused on
their potential as anti-cancer agents through their ability to inhibit
glycolysis (19)
. Although high concentrations of 5
mM could inhibit growth in vitro, similar plasma
concentrations had little effect on mouse tumors in vivo.
The LD50 was reached at daily doses 1.5 mmol/kg
(3
, 19)
. In our experiments, mice received a single dose
of 5FU plus two doses of FDG separated by 48 h, and there was no
significant increase in animal or tumor toxicity compared with that
measured in the model where animals received only 5FU (7)
.
However, if FDG was administered 24 h after 5FU and therefore just
24 h after the first FDG dose, then two of three animals died.
Otherwise, the dose we have used of 1.4 mmol/kg i.p. of FDG, which
produced a plasma concentration of 1.6 mM,
appears not to be significantly toxic. Furthermore, our unpublished
observations suggest that a lower dose of 1 mmol/kg provides sufficient
signal-to-noise ratio to detect FDM in RIF-1 and other murine
tumors of 1 g, and much lower doses may be possible in rat tumors,
which can be used at volumes of 5–10 g.
In conclusion, RIF-1 tumors are capable of forming considerable amounts
of FDM from FDG, and this may be detected by 19F
MRS in vivo. The rate and/or amount of FDM formation, but
not the total FDG or 19F signal, correlated
significantly with the response of the tumors to 5FU treatment.
Considerations of the known biochemical response of RIF-1 tumors to 5FU
suggest that decreases in the rate of formation of FDM reflect
decreases in the rate of glycolysis in these tumors. We are currently
aiming to determine whether: (a) FDM formation reflects HK
activity; and (b) FDM formation can predict tumor response
to other chemotherapeutic agents. If the latter is verified, then
19F MRS of FDG metabolism may prove to be a novel
means of predicting tumor response noninvasively, which would have
useful clinical applications. Indeed, because human tumors at
presentation tend to be quite large compared with animal tumors, this
would permit lower FDG doses to be used of 0.2
g/m2, thus decreasing the likelihood of any
toxicity.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by the Cancer Research
Campaign (CRC) Program Grant SP1971/0503. 
2 To whom requests for reprints should be
addressed, at Cancer Research Campaign Biomedical Magnetic Resonance
Research Unit, Department of Biochemistry and Immunology, St. George’s
Hospital Medical School, Cranmer Terrace, London SW17 0RE, United
Kingdom.
3 The abbreviations used are: PET, positron
emission tomography; FDG, 2'-fluoro-2'-deoxy-D-glucose;
FDG-6P, FDG-6-phosphate; FDM, 2'-fluoro-2'-deoxy-D-mannose;
FDM-6P, FDM-6-phosphate; FDG±P, FDG with/without phosphate; FDM±P,
FDM with/without phosphate; 5FU, 5-fluorouracil; MRS, magnetic
resonance spectroscopy; 6AN, 6-aminonicotinamide; RIF,
radiation-induced fibrosarcoma; AUC, area under the concentration-time
curve; 6PG, 6-phosphogluconate; PPP, pentose phosphate pathway; HK,
hexokinase; PGI, phosphoglucoisomerase; MXD, maximum decrease in tumor
volume; TV7, decrease in tumor volume at 7 days.
Received 10/25/99. Accepted 3/ 2/00.
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,
FDG±P; 
, FDM±P. Quantitative 19F MRS at 4.7 T of the
tumor extract showed that the amounts of FDG±P and FDM±P were 525 and
95 nmol, respectively, after 120 min.
,
and total 19F signal, •, r = 0.58, P = 0.17 and
r = 0.67, P = 0.10, respectively. b, FDM AUC,