Imaging colon cancer response following treatment with AZD1152: a preclinical analysis of [18F]fluoro-2-deoxyglucose and 3'-deoxy-3'-[18F]fluorothymidine imaging.
OBJECTIVE
To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [(18)F]-labeled fluoro-2-deoxyglucose, [(18)F]FDG, and/or 3'-deoxy-3'-[(18)F]fluorothymidine, [(18)F]FLT, PET imaging.


METHODS
AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [(18)F]FDG, and [(18)F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines.


RESULTS
Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [(18)F]FDG uptake did not demonstrate a treatment response. [(18)F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [(18)F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC(50) for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts.


CONCLUSIONS
AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [(18)F]FDG PET was inadequate in monitoring treatment response, [(18)F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [(18)F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Maxim A
MA
Moroz
Tatiana
T
Kochetkov
Shangde
S
Cai
Jiyuan
J
Wu
Mikhail
M
Shamis
Jayasree
J
Nair
Elisa
E
de Stanchina
Inna
I
Serganova
Gary K
GK
Schwartz
Debabrata
D
Banerjee
Joseph R
JR
Bertino
Ronald G
RG
Blasberg
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D005472:Fluorouracil / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D019394:Ki-67 Antigen / Q000032:analysis; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010755:Organophosphates / Q000627:therapeutic use*; D049268:Positron-Emission Tomography / Q000379:methods*; D011799:Quinazolines / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D013936:Thymidine / Q000096:biosynthesis; D013937:Thymidine Kinase / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019394:Ki-67 Antigen; D010755:Organophosphates; D011799:Quinazolines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D013937:Thymidine Kinase; C002854:alovudine; D005472:Fluorouracil; D013936:Thymidine; D008727:Methotrexate
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