Synthesis of 3′-deoxy-3′-[18F]fluoro-1-β-D- xylofurano-syluracil ([18F]-FMXU) for PET

Article abstract of DOI:10.1002/jlcr.1008

The synthesis of a pyrimidine analog, 3′-deoxy-3′-[ ¹⁸F]-fluoro-1-β-D-xylofuranosyluracil ([¹⁸F]-FMXU) is reported. 5-Methyluridine 1 was converted to its dimethoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′, 5′-

Full text of DOI:10.1002/jlcr.1008

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 941–950.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1008
Research Article
0
0
18
Synthesis of 3 -deoxy-3 -[ F]fluoro-1-b-d-xylofurano-
syluracil ([ F]-FMXU) for PET
18
M. M. Alauddin*, J. Balatoni and J. Gelovani
Department of Experimental Diagnostic Imaging, University of Texas MD Anderson
Cancer Center, Houston, TX, USA
Summary
0
0
18
The synthesis of a pyrimidine analog, 3 -deoxy-3 -[ F]-fluoro-1-b-d-xylofuranosylur-
acil ([ F]-FMXU) is reported. 5-Methyluridine 1 was converted to its di-
1
8
0
methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2 ,
0
0
5
-di-methoxytrityluridine 2 was converted to its 3 -triflate 4 followed by derivatization
3
to the respective N -t-Boc product 5. The triflate 5 was reacted with tetrabutylammo-
8
nium[ F]fluoride to produce 6, which by acid hydrolysis yielded compound 7. The
1
1
8
crude preparation was purified by HPLC to obtain the desired product [ F]-FMXU.
The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33%
in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/
mmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of
bombardment (EOB). Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: fluorine-18; nucleoside; PET
Introduction
We and others have been developing and testing several radiofluorinated
pyrimidine nucleoside analogs as potential agents for imaging tumor
1
–8
proliferative activity or HSV-tk reporter gene expression.
fluorinated analogs of pyrimidine nucleosides have been synthesized and
Initially, many
9
–13
0
studied as potential antitumor and antiviral agents.
Among these, 2 -
0
deoxy-2 -fluoro-5-methyl-1-b-d-arabinofuranosyluracil (FMAU) and other 5-
substituted derivatives are known to be phosphorylated by human and other
mammalian nucleoside kinases including thymidine kinase TK1 and TK2, as
well as viral kinase such as herpes simplex virus (HSV) type 1 and 2, and
*Correspondence to: Mian M. Alauddin, 1515 Holcombe Blvd. T8.3895, Houston, TX 77030, USA.
E-mail: alauddin@di.mdacc.tmc.edu
Contract/grant sponsor: The University of Texas
Copyright # 2005 John Wiley & Sons, Ltd.
Received 12 May 2005
Revised 6 July 2005
Accepted 8 August 2005

9
42
M. M. ALAUDDIN ET AL.
11 18
In particular, C and F radiolabeled FMAU is
14,15
hepatitis B virus.
currently undergoing clinical studies in multiple centers for imaging tumor
1
6–18
0
0
proliferation in a variety of cancer types.
Also, 2 -deoxy-2 -fluoro-5-
methyl-1-b-d-ribofuranosyluracil (FMRU) and 5-substituted analogs have
been synthesized and tested as potential imaging agents for tumor prolifera-
1
9,20
0
tion.
The only nucleoside analog radiolabeled in the 3 -position reported
18
0
18
to date is 3 -[ F]-fluoro-3 -deoxy-thymidine ([ F]-FLT), which is currently
under clinical investigation as a potential PET imaging agent for tumor
0
2
1,22
0
proliferation.
0
However, no information is available regarding the 3 -
deoxy-3 -fluoro-5-methyl-1-b-d-xylofuranosyluracil (FMXU), no radiolabel-
ing procedure has been described in the literature, and the biological
0
0
properties of this compound are unknown. Recently, 3 -deoxy-3 -fluoro-
xylo-cytidine derivatives have been reported to exhibit antiviral activity
23
against hepatitis C virus. This prompted us to attempt the synthesis and
0
radiofluorination of pyrimidine nucleosides in the 3 -fluoro xylo-configuration.
0
0
In contrast to 2 -deoxy-2 -fluoro-arabino-pyrimidine nucleosides, in which the
0
direct radiolabeling of 2 -position in the arabino-configuration is not feasible
0
using a one step radiolabeling procedure, the direct fluorination in the 3 -xylo
configuration of the sugar moiety of a pyrimidine nucleoside is feasible as
0
0
described in the current report. Using the protected nucleoside precursor 2 ,5 -
0
3
di-methoxytrityl-3 -trifluoromethanesulfonyl-N -t-Boc-5-methyluridine and
conventional nucleophilic radiofluorination and purification, we have
0
18
0
synthesized 3 -deoxy-3 -[ F]fluoro-5-methyl-1-b-d-xylofuranosyluracil in high
yield, high specific activity and purity.
Results and discussion
Figure 1 represents the scheme for the synthesis of the pyrimidine nucleoside
analog, FMXU. Compounds 2 and 3 were prepared from 5-methyluridine
4
following a method similar to the synthesis of fluoro-adenosine analogs.
2
Reaction of 5-methyluridine with methoxytrityl chloride (MTrCl) in pyridine
in the presence of N,N-dimethylaminopyridine (DMAP) produced a mixture
of 2 compounds, which were separated by column chromatography. The early
0
0
eluting compound was the desired product 2 ,5 -di-methoxytrityl derivative 2.
Compounds 2 and 3 were isolated in 50% and 28% yields, respectively, with a
combined yield of 78%. The chromatographic elution of these compounds was
24
similar to that of adenosine derivatives. Both compounds were characterized
1
by H NMR spectroscopy, and compound 2 was further analyzed by high-
resolution mass spectrometry.
Compound 4 was prepared by reaction of 2 with trifluoromethanesulfonic
anhydride ((Tf) O) in pyridine at room temperature. However, addition of
2
(
Tf) O should be performed at 08C, since it is highly reactive and exothermic.
2
There after the reaction may proceed at room temperature. Yield in this step
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 941–950

18
(
[
F]-FMXU) FOR PET
943
O
N
O
O
N
CH3
MTrCl
CH3
HN
CH3
CH3
CH3
HN
HN
+
O
O
N
O
Pyridine
HO
MTrO
MTrO
MTrO
MTrO
O
O
O
HO OH
HO OMTr
MTrO OH
1
2
3
O
O
O
CH3
CH3
Boc
N
HN
HN
(
Boc ) O
(
Tf ) O
2
2
O
N
O
N
O
N
Pyridine
Pyridine
MTrO
MTrO
O
O
O
HO OMTr
TfO OMTr
TfO OMTr
2
4
5
O
O
O
Boc
CH3
Boc
CH3
N
O
N
O
HN
F-
HCl
O
N
O
N
O
N
MeCN
MTrO
HO
O
F
F
TfO OMTr
OMTr
OH
5
6
7
0
0
Figure 1. Synthetic scheme of 3 -deoxy-3 -fluoro-5-methyl-1-b-d-xylofuranosy-
luracil (FMXU)
was 82% after chromatographic purification. This compound was character-
1
ized by H and F NMR spectroscopy, and high-resolution mass spectro-
19
0
metry. Chemical shift of the 3 H was significantly changed from 2.79 to
1
.72 ppm due to the electronegativity of the sulfonic ester. F NMR spectrum
9
4
showed a singlet at ꢀ75.678 ppm, consistent with those of other sugar
triflates.
2
4
Compound 5 was prepared by reaction of 4 with di-tert-butyl dicarbonate
Boc) in pyridine at room temperature. Yield in this step was 60% after
(
1
chromatographic purification. This compound was characterized by H and
1
9
19
F NMR spectroscopy, and high-resolution mass spectrometry. F NMR
spectra showed a singlet at ꢀ75.678 ppm.
0
Fluorination of the triflate precursor 5 with n-Bu NF produced the 3 -
4
0
deoxy-3 -fluoro-5-methyl-1-b-d-xylofuranosyluracil derivative 6 in 40–50%
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 941–950

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M. M. ALAUDDIN ET AL.
yields. Compound 6 was purified by column chromatography, and character-
1
ized by H and F NMR spectroscopy, and high-resolution mass spectro-
19
1
metry. H NMR spectrum of 6 was identical with that reported for 3 -deoxy-
0
0
25
3
-fluoro-1-b-d-xylofuranosyluracil (FXU), especially the coupling between
fluorine and 4 H vs fluorine and 2 H. The coupling constant between F and
0
0
0
0
4
H (34 Hz) was significantly larger than that between F and 2 H (16 Hz),
0
which suggests the trans orientation of F and 4 H. The coupling constant
0
between F and 3 H was 50.7 Hz, a typical geminal coupling between F and H.
1
Comparing the H NMR spectrum with that of FXU, the orientation of F in
2
5 19
compound 6 appeared to be in the xylo-configuration.
F NMR spectrum
(decoupled) of 6 showed a single peak at ꢀ198.38 ppm, and the coupled
spectrum showed a multiplate (doublet of doublet of doublet) with coupling
1
constants as observed in H NMR spectrum.
Compound 7 (FMXU) was prepared by acid hydrolysis of the protecting
2
groups from 6 following the method reported earlier. Both t-Boc and
4
methoxytrityl groups were hydrolyzed under the same reaction condition. The
1
crude product was purified by HPLC and characterized by H and F NMR
19
1
spectroscopy, and high-resolution mass spectrometry. H NMR spectrum of
0
FMXU showed a typical coupling of 3 H and F (geminal coupling) with
0
coupling constant 50.7 Hz. The vicinal coupling constant between F and 4 H
0
19
was larger than that of F and 2 H. F NMR spectrum showed 8 peaks
(a doublet of doublet of doublets).
Radiolabeled compound 7 was prepared by fluorination of the triflate
1
8
precursor 5 with n-Bu N F, prepared in situ from n-Bu NHCO and aqueous
4
4
3
1
H F. Either Bu N F or K F can be used as fluorinating agent; however,
1
K F requires kryptofix to generate naked fluoride. Bu N F has advantages,
8
18
18
4
8
18
4
such as, it is more soluble in organic solvents, and fluorination takes place at
lower temperature. In this reaction 0.40 ml (1% solution, ꢁ7 mmol) of n-
Bu NHCO was used based on our earlier experience of an optimum
4
3
1
,2,24
18
quantity.
Evaporation of water from the aqueous Bu N F and
4
anhydrous conditions are critical for the fluorination reaction. Overheating
1
8
(
>808C) of Bu N F resulted in low yields of the desired product. Higher
4
1
yields were obtained when drying the Bu N F was performed by adding
8
4
multiple sequential aliquots of acetonitrile during azeotropic evaporation of
1
8
18
water from aqueous Bu N F. Unreacted [ F]-fluoride was removed by
4
passing the crude reaction mixture through a silica-gel cartridge (900 mg,
Alltech), and the product was eluted with 10% methanol in dichloromethane.
18
After solvent evaporation the recovered F-labeled compound 6 was readily
hydrolyzed with acid, and the desired labeled nucleoside 7 isolated by HPLC
purification using 10% MeCN. Figure 2 represents a typical purification of
1
[
8
18
F]-FMXU. The radioactive peak at 10 min is the desired product [ F]-
FMXU. The UV peak corresponding to the radioactive peak was quite low,
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 941–950

18
(
[
F]-FMXU) FOR PET
945
1
8
Figure 2. HPLC purification of [ F]-FMXU: Semi-prep C Column; 10%
1
8
0
MeCN/H O; flow 4.0 ml/min. Capacity factor ðk Þ ¼ 3:3
2
almost undetectable since there was no carrier added in the synthesis. The
product could also be purified by HPLC using 10% ethanol in water. In this
18
solvent system [ F]-FMXU eluted at 12 min with the same flow rate as 10%
MeCN.
The radiochemical yield of this synthesis was 25–40% (d. c.) with an average
of 33 ꢂ 7% in four runs. The radiochemical purity was >99% with specific
activity >74 GBq/mmol. The specific activity in this no-carrier-added synthesis
1
8
18
was comparable with that of [ F]-FMAU and 2-fold higher than [ F]-FLT
(
37 GBq/mmol), which are produced for PET imaging of animals and cancer
1
,4
patients. The synthesis time was 67–75 min from end of bombardment
EOB). In a representative synthesis, 5 mCi (185 MBq) of labeled product 7
(
1
8
was obtained starting from 20 mCi (740 MBq) of [ F]-fluoride. Analytical
sample of 7 (HPLC) showed a single radioactive peak that co-eluted at 7.5 min
with an authentic sample (Figure 3).
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 941–950

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M. M. ALAUDDIN ET AL.
18
Figure 3. HPLC chromatogram of [ F]-FMXU, co-injected with standard
FMXU: Analytical C18 Column; 10% MeCN/H O; flow 1.0 ml/min. Capacity
2
0
factor ðk Þ ¼ 2:2
Experimental
Reagents and instrumentation
All reagents and solvents were purchased from Aldrich Chemical Co.
(Milwaukee, WI), and used without further purification. Solid phase
extraction cartridges (silica gel, 900 mg) were purchased from Alltech
Associates (Deerfield, IL).
Thin layer chromatography (TLC) was performed on pre-coated Kieselgel
1
9
6
0 F254 (Merck) glass plates. Proton and F NMR spectra were recorded on
a Brucker 300 MHz spectrometer using tetramethylsilane as an internal
reference and hexafluorobenzene as an external reference, respectively. High-
resolution mass spectra (MS) were obtained on a Bruker BioTOF II mass
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 941–950

18
(
[
F]-FMXU) FOR PET
947
spectrometer at the University of Minnesota using electrospray ionization
(ESI) technique.
High-performance liquid chromatography (HPLC) was performed on a
1
2
100 series pump (Agilent, Germany), with built in UV detector operated at
54 nm, and a radioactivity detector with single-channel analyzer (Bioscan,
Washington DC) using a semi-preparative C18 reverse phase column (Alltech,
Econosil, 10 ꢃ 250 mm, Deerfield, IL) and an analytical C18 column (Rainin,
Microsorb-MV, 4.6 ꢃ 250 mm, Emeryville, CA). A acetonitrile/water (MeCN/
H O) solvent system (10% MeCN) was used for purification of the
2
radiolabeled nucleoside, and for quality control analysis on analytical HPLC.
0
0
0
Preparation of 2 ,5 -di-methoxytrityl-3 -hydroxy-5-methyluridine: 2
Methyluridine (520 mg, 2.02 mmol), methoxytrityl chloride (1.4 g, 4.5 mmol)
and N,N-dimethylaminopyridine (250 mg, 2.04 mmol) were taken into a dry
flask under argon. Pyridine (10 ml) was added and the mixture was heated with
stirring at 908C for 16 h when TLC showed no starting material remained. The
reaction mixture was cooled to room temperature and solvent was evaporated
under vacuum. The residue was dissolved in 50% EtOAc/hexane (250 ml) and
the solution washed with water (3 ꢃ 250 ml). The organic phase was dried in
MgSO and solvent was evaporated to dryness. The crude product was
4
purified on a silica-gel column and eluted with 30% ethyl acetate in hexane.
1
The solvent was evaporated to get the desired product in 50% yield. H NMR
(
CDCl ) d: 8.59 (s, 1 H, NH), 6.69–7.51 (m, 29 H, aromatic & C H), 6.58 (d,
3
6
0
0
0
1
H, J ¼ 6 Hz, 1 H), 4.49ꢀ4.53 (m, 1 H, 2 H), 3.98 (s, 1 H, 4 H), 3.78 (s, 6 H,
0
0
OMe), 3.25 (d, 1 H, Jgem ¼ 9:0 Hz, 5 H), 2.99, (d, 1 H, J
2.79 (d, 1 H, J ¼ 3 Hz, 3 H), 1.22 (s, 3 H, Me). High-resolution MS: M+Na,
calculated 825.3146; found 825.3150.
¼ 9:0 Hz, 5 H),
gem
0
0
0
0
Preparation of 2 ,5 -di-methoxytrityl-3 -trifluoromethanesulfonyl-5-methyluri-
dine: 4
Compound 2 (0.450 g, 0.56 mmol) was dissolved in pyridine (7 ml) under argon
and cooled in an ice bath. Trifluoromethanesulfonic anhydride (0.2 ml, 2
equiv) was added and the reaction mixture was stirred for 10 min in the cold
and subsequently for 50 min at room temperature when TLC showed no
starting material remained. The reaction mixture was quenched with cold
water (50 ml) and extracted with 50% EtOAc/hexane (3 ꢃ 50 ml). The organic
extract was dried (MgSO ) and evaporated to dryness, and the crude product
4
purified by chromatography on a silica-gel column using 40% ethyl acetate in
1
hexane. Pure compound (540 mg) was obtained in 82% yield. H NMR
(
CDCl ) d: 8.45 (s, 1 H, NH), 6.70–7.45 (m, 29 H, aromatic & C H), 6.49 (d,
H, J ¼ 9:0 Hz, 1 H), 4.69–4.73 (m, 1 H, 2 H), 4.29 (d, 1 H, J ¼ 3 Hz, 3 H),
3
6
0
0
0
1
Copyright # 2005 John Wiley & Sons, Ltd.
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M. M. ALAUDDIN ET AL.
0
4
.24 (s, 1 H, 4 H), 3.82 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.36 (d, 1 H,
19
0
0
Jgem ¼ 9:0 Hz, 5 H), 3.09 (d, J
¼ 9:0 Hz, 5 H), 1.37 (s, 3 H, Me). F NMR
gem
(d): ꢀ75.678 (s). High-resolution MS: M+Na, calculated 957.2639; found
9
57.2618.
0
0
0
3
Preparation of 2 ,5 -di-methoxytrityl-3 -trifluoromethanesulfonyl-N -t-Boc-5-
methyluridine: 5
Compound 4 (140 mg, 0.15 mmol) and di-tert-butyl dicarbonate (120 mg, 3.6
equiv) were taken into a flask under argon. Dry pyridine (5 ml) was added and
the reaction mixture was stirred at room temperature for 16 h when TLC
showed no starting material remained. Solvent was evaporated under high
vacuum, and the residue was dissolved in 50% EtOAc/hexane (40 ml), then
washed with water (3 ꢃ 40 ml). The organic phase was dried (MgSO ) and
4
evaporated to isolate the crude product, which was purified by flash
chromatography on silica-gel column using 25% EtOAc/hexane. Pure
1
compound (0.103 g) was obtained in 62% yield. H NMR (CDCl ) d: 6.72–
3
0
7
.43 (m, 29 H, aromatic & C H), 6.49 (d, 1 H, J ¼ 8:1 Hz, 1 H), 4.69–4.73
6
0
0
0
(
m, 1 H, 2 H), 4.24–4.29 (m, 2 H, 3 H & 4 H), 3.80 (s, 3 H, OMe), 3.74 (s, 3 H,
0
0
OMe), 3.38 (d, 1 H, Jgem¼ 9:0 Hz 5 H), 3.0 (d 1 H, J ¼ 9:0 Hz, 5 H), 1.62
gem
19
(
s, 3 H, Me), 1.52 (s, 9 H, t-but). F NMR (d): ꢀ75.678 (s). High-resolution
MS: M+Na, calculated 1057.3164; found 1057.3201.
0
0
0
3
Preparation of 2 ,5 -di-methoxytrityl-3 -fluoro-N -Boc-5-methyl-1-b-d-xylofur-
anosyluracil: 6
Compound 5 (34 mg, 0.033 mmol) was dissolved in dry MeCN (2.0 ml) in a
sealed V-vial. To the above solution, n-Bu NF (1 M, 70 ml) was added and the
4
mixture was heated for 20 min at 72–748C in a heating block. The reaction
mixture was cooled to room temperature. The solvent was evaporated in a
stream of air and the residue purified on a short silica-gel column using 30%
ethyl acetate in hexane. Pure compound 6 (14 mg) was obtained in 46% yield.
1
H NMR (CDCl ) d: 6.79–7.50 (m, 29 H, aromatic & C H), 6.48 (d, 1 H,
3
6
0
0
0
J ¼ 2:1 Hz 1 H), 4.07–4.13 (m, 2 H, 2 & 4 H), 3.78 (s, 3 H, OMe), 3.77 (s, 3 H,
OMe), 3.55 (dd, 1 H, J ¼ 50:7 and 1.8 Hz, 3 H), 3.36–3.42 (m, 1 H, 5 H),
0
0
0
19
3
.18–3.23 (m, 1 H, 5 H), 1.79 (s, 1 H, CH ), 1.65 (s, 9 H, t-But).
3
F
NMR (d): ꢀ198.38. High-resolution MS: M+Na, calculated 927.3627; found
27.3659.
9
0
0
Preparation of 3 -deoxy-3 -fluoro-5-methyl-1-b-d-xylofuranosyluracil: 7
Compound 6 (30 mg) was placed in a small flask and dissolved in methanol
(5 ml). Hydrochloric acid (1 M, 0.3 ml) was added to the above solution and
refluxed for 10 min. The reaction mixture was cooled and solvent evaporated.
Copyright # 2005 John Wiley & Sons, Ltd.
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(
[
F]-FMXU) FOR PET
949
The crude product was washed with CH Cl (3 ꢃ 10 ml), which was discarded,
2
2
and the residue was purified by HPLC to obtain the unlabeled FMXU (6 mg)
1
in 70% yield. H NMR (D O) d: 7.45 (s, 1 H, C H), 5.82 (d, 1 H, J ¼ 2:1 Hz,
2
6
0
0
0
1
H), 5.01 (dd, 1 H, J ¼ 50:7 and 3 Hz, 3 H), 4.47 (d, 1 H, J ¼ 15 Hz, 2 H),
0
0
4
.37 (dt, J ¼ 30 Hz, 4 H), 3.92–3.96 (m, 2 H, 5 H), 1.79 (s, 1 H, CH ). High-
3
resolution MS: M+Na, calculated 283.0701 found 283.0718.
0
0
18
Preparation of 3 -deoxy-3 [ F]fluoro-5-methyl-1-b-d-xylofuranosyluracil
1
The aqueous [ F]fluoride was trapped in anion exchange cartridge (ABX,
8
Germany) and eluted with a solution of n-Bu NHCO (400 ml, 1% by wt) into
4
3
a V-vial and the solution evaporated azeotropically with acetonitrile (1.0 ml) to
1
8
dryness at 79–808C under a stream of argon. To the dried n-Bu N F, a
4
solution of 5 (5–6 mg) in anhydrous acetonitrile (0.5 ml) was added, and the
mixture was heated at 79–808C for 10 min. The reaction mixture was cooled,
passed through a silica-gel cartridge (Alltech), and eluted with 10% methanol
in dichloromethane (2.5 ml). After evaporation of the solvent with a stream of
argon at ꢁ808C, the residue was dissolved in methanol (0.4 ml). Hydrochloric
acid solution in methanol (1 N, 0.1 ml) was added and the mixture was refluxed
for 10 min. The crude mixture was neutralized with 1 N sodium bicarbonate
solution (0.1 ml), diluted with HPLC solvent (1.0 ml) and purified by HPLC.
The desired product was isolated and radioactivity was measured in a dose
calibrator (Capintec, Ramsey, NJ). The product was co-injected with an
authentic unlabeled sample onto an analytical column to confirm its identity.
Conclusion
0
0
18
We have developed a synthesis of a new radiotracer 3 -deoxy-3 -[ F]fluoro-5-
18
methyl-1-b-d-xylofuranosyluracil ([ F]-FMXU) at high yield, high specific
activity and purity. The described method may be suitable for the preparation
0
0
18
of other 3 -deoxy-3 -[ F]fluoro-xylo-nucleoside analogs.
Acknowledgements
This work was supported by start-up funds from The University of Texas, MD
Anderson Cancer Center.
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