Metabolomics Strategy Reveals Subpopulation of Liposarcomas Sensitive to Gemcitabine Treatment
| العنوان: | Metabolomics Strategy Reveals Subpopulation of Liposarcomas Sensitive to Gemcitabine Treatment |
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| المؤلفون: | Fritz C. Eilber, Ethan Ahler, Owen N. Witte, Kathleen B. Smith, David Nathanson, Mirielle Riedinger, William D. Tap, Hong Wu, Brenna M. Tam, Daniel Braas, Heather R. Christofk, Matthias R. Benz |
| المصدر: | Cancer Discovery. 2:1109-1117 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Antimetabolites, Antineoplastic, Liposarcoma, Biology, Deoxycytidine, Article, Nucleoside salvage, Mice, chemistry.chemical_compound, Tandem Mass Spectrometry, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Metabolomics, neoplasms, Nucleoside analogue, Cancer, Deoxycytidine kinase, medicine.disease, Xenograft Model Antitumor Assays, Gemcitabine, body regions, Oncology, chemistry, Immunology, Cancer research, Female, Chromatography, Liquid, medicine.drug |
| الوصف: | Unlike many cancers that exhibit glycolytic metabolism, high-grade liposarcomas often exhibit low 2[18F]fluoro-2-deoxy-d-glucose uptake by positron emission tomography (PET), despite rapid tumor growth. Here, we used liquid chromatography tandem mass spectrometry to identify carbon sources taken up by liposarcoma cell lines derived from xenograft tumors in patients. Interestingly, we found that liposarcoma cell lines consume nucleosides from culture media, suggesting nucleoside salvage pathway activity. The nucleoside salvage pathway is dependent on deoxycytidine kinase (dCK) and can be imaged in vivo by PET with 1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine (FAC). We found that liposarcoma cell lines and xenograft tumors exhibit dCK activity and dCK-dependent FAC uptake in vitro and in vivo. In addition, liposarcoma cell lines and xenograft tumors are sensitive to treatment with the nucleoside analogue prodrug gemcitabine, and gemcitabine sensitivity is dependent on dCK expression. Elevated dCK activity is evident in 7 of 68 clinical liposarcoma samples analyzed. These data suggest that a subpopulation of liposarcoma patients have tumors with nucleoside salvage pathway activity that can be identified noninvasively using [18F]-FAC–PET and targeted using gemcitabine. Significance: Patients with high-grade liposarcoma have poor prognoses and often fail to respond to chemotherapy. This report identifies elevated nucleoside salvage activity in a subset of liposarcomas that are identifiable using noninvasive PET imaging with FAC and that are sensitive to gemcitabine. Thus, we suggest a new treatment paradigm for liposarcoma patients that uses [18F]-FAC-PET in the clinic to delineate gemcitabine responders from nonresponders. Cancer Discov; 2(12); 1109–17. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 1065 |
| تدمد: | 2159-8290 2159-8274 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1e9cde033ccb0e7e266f1e39643e3ad https://doi.org/10.1158/2159-8290.cd-12-0197 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a1e9cde033ccb0e7e266f1e39643e3ad |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
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