Imaging colon cancer response following treatment with AZD1152: A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging

Maxim A. Moroz, Tatiana Kochetkov, Shangde Cai, Jiyuan Wu, Mikhail Shamis, Jayasree Nair, Elisa De Stanchina, Inna Serganova, Gary K. Schwartz, Debabrata Banerjee, Joseph Bertino, Ronald G. Blasberg

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [ 18F]FLT, PET imaging. Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]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, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [ 18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 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 [18F]FDG PET was inadequate in monitoring treatment response, [18F]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 [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.

Original languageEnglish (US)
Pages (from-to)1099-1110
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number5
DOIs
StatePublished - Mar 1 2011

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Deoxyglucose
Heterografts
Colonic Neoplasms
Fluorodeoxyglucose F18
HCT116 Cells
Thymidine
Aurora Kinase B
alovudine
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
Thymidine Kinase
Methotrexate
Fluorouracil
Neoplasms
Research Design
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Moroz, Maxim A. ; Kochetkov, Tatiana ; Cai, Shangde ; Wu, Jiyuan ; Shamis, Mikhail ; Nair, Jayasree ; De Stanchina, Elisa ; Serganova, Inna ; Schwartz, Gary K. ; Banerjee, Debabrata ; Bertino, Joseph ; Blasberg, Ronald G. / Imaging colon cancer response following treatment with AZD1152 : A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 5. pp. 1099-1110.
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abstract = "Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [ 18F]FLT, PET imaging. Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]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, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20{\%} of control values in AZD1152-treated HCT116 xenografts, whereas [ 18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 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 [18F]FDG PET was inadequate in monitoring treatment response, [18F]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 [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.",
author = "Moroz, {Maxim A.} and Tatiana Kochetkov and Shangde Cai and Jiyuan Wu and Mikhail Shamis and Jayasree Nair and {De Stanchina}, Elisa and Inna Serganova and Schwartz, {Gary K.} and Debabrata Banerjee and Joseph Bertino and Blasberg, {Ronald G.}",
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Moroz, MA, Kochetkov, T, Cai, S, Wu, J, Shamis, M, Nair, J, De Stanchina, E, Serganova, I, Schwartz, GK, Banerjee, D, Bertino, J & Blasberg, RG 2011, 'Imaging colon cancer response following treatment with AZD1152: A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging', Clinical Cancer Research, vol. 17, no. 5, pp. 1099-1110. https://doi.org/10.1158/1078-0432.CCR-10-1430

Imaging colon cancer response following treatment with AZD1152 : A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging. / Moroz, Maxim A.; Kochetkov, Tatiana; Cai, Shangde; Wu, Jiyuan; Shamis, Mikhail; Nair, Jayasree; De Stanchina, Elisa; Serganova, Inna; Schwartz, Gary K.; Banerjee, Debabrata; Bertino, Joseph; Blasberg, Ronald G.

In: Clinical Cancer Research, Vol. 17, No. 5, 01.03.2011, p. 1099-1110.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Imaging colon cancer response following treatment with AZD1152

T2 - A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging

AU - Moroz, Maxim A.

AU - Kochetkov, Tatiana

AU - Cai, Shangde

AU - Wu, Jiyuan

AU - Shamis, Mikhail

AU - Nair, Jayasree

AU - De Stanchina, Elisa

AU - Serganova, Inna

AU - Schwartz, Gary K.

AU - Banerjee, Debabrata

AU - Bertino, Joseph

AU - Blasberg, Ronald G.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [ 18F]FLT, PET imaging. Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]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, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [ 18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 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 [18F]FDG PET was inadequate in monitoring treatment response, [18F]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 [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.

AB - Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [ 18F]FLT, PET imaging. Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]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, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [ 18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 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 [18F]FDG PET was inadequate in monitoring treatment response, [18F]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 [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.

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