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[(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma

Salem, Nicolas
http://rave.ohiolink.edu/etdc/view?acc_num=case1238772847

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Hepatocellular carcinoma (HCC) is a deadly cancer. The poor survival rate is a consequence of the absence of efficient chemotherapeutic agents and the fact that this cancer is often asymptomatic until advanced stages. In this work, the woodchuck model of HCC was used to investigate the metabolism of [(methyl)1-11C]acetate (Act). This positron emission tomography (PET) radiotracer has shown promises for detecting HCC in humans, but its metabolism is currently unknown. PET studies with 2-deoxy-2[18F]fluoro-D-glucose (FDG) first showed FDG uptake in four moderately- to poorly-differentiated tumors, which had decreased glucose-6-phosphatase to hexokinase activity ratio compared to peritumoral liver tissues. Act and [(N-methyl)11C]choline (CCho) were shown to be more sensitive than FDG for detecting HCC. Pharmacokinetic modeling showed that a two-tissue compartmental model with four rate-constants better describes the Act metabolism in HCCs with high Act uptake. A two-tissue compartmental model with three rate-constants was sufficient to describe Act metabolism in peritumoral liver tissues or in HCCs with low Act uptake. The local hepatic metabolic rate of Act utilization (LHMRAct) could quantitatively distinguish between peritumoral liver tissues or HCCs with low Act uptake and HCCs with high Act uptake. Peritumoral liver tissues and HCCs with low Act uptake were associated with high venous clearance and decreased transport of radioactive species into the second tissue compartment. The opposite was seen in HCCs with high Act uptake. In vivo studies with 14C-Act showed that high Act uptake was associated with increased incorporation of the 14C label into lipids, with phosphatidylcholine being the main metabolite. In vitro experiments showed that radiolabeled acetate was preferentially converted to radioactive carbon dioxide (CO2) or retained in water-soluble compounds in hepatocytes whereas WCH-17 cells, which are derived from an adult woodchuck hepatoma, predominantly incorporated the 14C label from 14C-Act into lipid-soluble compounds, with PC being the predominant metabolite. Rapamycin treatment was finally shown to decrease the incorporation of 14C-Act into lipids in WCH-17 cells. This research provides a basis for further investigation on the usefulness of Act for detecting HCC and for supporting the development of novel chemotherapeutic drugs targeting lipid synthesis in HCC.
David Wilson, L (Committee Chair)
Zhenghong Lee (Advisor)
Gerald Saidel, M (Committee Member)
Stephen Previs (Committee Member)
277 p.
Oncology
Woodchuck; Marmota monax; hepatocellular carcinoma; liver cancer; PET; acetate; glucose; choline; metabolism

Recommended Citations

Citations

  • Salem, N. (2009). [(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1238772847

    APA Style (7th edition)

  • Salem, Nicolas. [(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1238772847.

    MLA Style (8th edition)

  • Salem, Nicolas. "[(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1238772847

    Chicago Manual of Style (17th edition)

case1238772847
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© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.