carbon-11-acetate and Disease-Models--Animal

Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.. 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.. Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.. Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

Topics: Acetates; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Carbon; Carcinoma, Hepatocellular; Disease Models, Animal; Fluorodeoxyglucose F18; Liver Neoplasms; Mice; Mice, Knockout; Multimodal Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, X-Ray Computed

PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, 18F-FDG and 11C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 microg dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received 18F-FDG, whereas the remaining eight animals were administered 11C-acetate. Rats were sacrificed at 120 min post-injection of 18F-FDG or 30 min post-injection of 11C-acetate. Pretreatment of the mouse model using DHT (200 microg of DHT in 0.1 mL of sunflower seed oil) or DES (200 microg of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in 18F-FDG study, while there was no significant difference in 11C-acetate uptake. These results indicate that changes in serum testosterone levels influence 18F-FDG uptake in the prostate gland, which is closely tied to glucose metabolism, within 24 hours of treatment and in the prostate tumor within 1 week. These early metabolic changes could enable monitoring metabolic changes in prostate tumor following treatment by imaging using 18F-FDG PET. Further studies are needed to clarify the reason for the insensitivity of 11C-acetate for measuring metabolic change in prostate tumor.

Topics: Acetates; Androgen Antagonists; Androgens; Animals; Carbon; Diethylstilbestrol; Dihydrotestosterone; Disease Models, Animal; Fluorodeoxyglucose F18; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Mice, Nude; Neoplasm Transplantation; Organ Specificity; Prostate; Prostatic Neoplasms; Radiopharmaceuticals; Rats; Tissue Distribution; Tomography, Emission-Computed