Imaging colon cancer response following treatment with AZD1152: A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging Journal Article
| Authors: | Moroz, M. A.; Kochetkov, T.; Cai, S.; Wu, J.; Shamis, M.; Nair, J.; de Stanchina, E.; Serganova, I.; Schwartz, G. K.; Banerjee, D.; Bertino, J. R.; Blasberg, R. G. |
| Article Title: | Imaging colon cancer response following treatment with AZD1152: A preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]fluorothymidine imaging |
| 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. ©2011 AACR. |
| Keywords: | controlled study; protein expression; human cell; fluorouracil; drug efficacy; nonhuman; methotrexate; positron emission tomography; mouse; animal tissue; multiple cycle treatment; tumor volume; animal experiment; animal model; antineoplastic activity; cancer cell culture; tumor xenograft; strain difference; colorectal carcinoma; drug response; fluorodeoxyglucose f 18; thymidine kinase; drug monitoring; 3' fluorothymidine f 18; drug sensitivity; non invasive measurement; cell strain hct116; barasertib |
| Journal Title: | Clinical Cancer Research |
| Volume: | 17 |
| Issue: | 5 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-03-01 |
| Start Page: | 1099 |
| End Page: | 1110 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-10-1430 |
| PROVIDER: | scopus |
| PMCID: | PMC3079195 |
| PUBMED: | 21245090 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus" |
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