No abstract

Trans-1-amino-3-18 F-fluorocyclobutanecarboxylic acid (anti-18 F-FACBC) is an amino acid PET tracer that has shown promise for visualizing prostate cancer. Therefore, we aimed to clarify the anti-18 F-FACBC transport mechanism in prostate cancer cells. We also studied the fate of anti-18 F-FACBC after it is transported into cells. Methods: For convenience, because of their longer half-lives, 14 C compounds were used instead of 18 F-labeled tracers. Trans-1-amino-3-fluoro-1-14 C-cyclobutanecarboxylic acid ( 14 C-FACBC) uptake was examined in human prostate cancer DU145 cells with the following substrates of amino acid transporters: a-(methylamino) isobutyric acid (a system A-specific substrate) and 2-amino-2-norbornanecarboxylic acid (a system L-specific substrate). The messenger RNA expression of amino acid transporters in human prostate cancer specimens was analyzed by complementary DNA microarray and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Gene expression in DU145 cells was analyzed by qRT-PCR. We also examined the knockdown effect of the amino acid transporters system ASC transporter 2 (ASCT2) and sodium-coupled neutral amino acid transporter 2 (SNAT2) on 14 C-FACBC uptake. In addition, the possibility of 14 C-FACBC incorporation into proteins was examined. Results: 14 C-FACBC uptake by DU145 cells was markedly decreased to approximately 20% in the absence of Na 1 , compared with that in its presence, indicating that Na 1 -dependent transporters are mainly responsible for the uptake of this tracer. Moreover, 2-amino-2-norbornanecarboxylic acid inhibited the transport of 14 C-FACBC to the basal level in Na 1 -free buffer. In contrast, a-(methylamino) isobutyric acid did not inhibit 14 C-FACBC accumulation in DU145 cells. Human prostate tumor specimens and DU145 cells had similar messenger RNA expression patterns of amino acid transporter genes. Although SNAT2 and ASCT2 are 2 major amino acid transporters expressed in prostate tumor tissues and DU145 cells, ASCT2 knockdown using small interfering RNA was more effective in lowering 14 C-FACBC transport than SNAT2. Almost all intracellular 14 C-FACBC was recovered from the nonprotein fraction. Conclusion: ASCT2, which is a Na 1 -dependent amino acid transporter, and to a lesser extent Na 1 -independent transporters play a role in the uptake of 14 C-FACBC by DU145 cells. Among the Na 1 -independent transporters, system L transporters are also involved in the transport of 14 C-FACBC. Moreover, 14 C-FACBC is not incorporated into proteins in cells. These findings suggest a possible mechanism of anti-18 F-FACBC PET for prostate cancer.

No abstract

Peritoneal dissemination is a common cause of death from gastrointestinal cancers and is difficult to treat using current therapeutic options, particularly late-phase disease. Here, we investigated the feasibility of integrated therapy using 64Cu-intraperitoneal radioimmunotherapy (ipRIT), alone or in combination with positron emission tomography (PET)-guided surgery using a theranostic agent (64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab) to treat early- and late-phase peritoneal dissemination in mouse models. In this study, we utilized the OpenPET system, which has open space for conducting surgery while monitoring objects at high resolution in real time, as a novel approach to make PET-guided surgery feasible. 64Cu-ipRIT with cetuximab inhibited tumor growth and prolonged survival with little toxicity in mice with early-phase peritoneal dissemination of small lesions. For late-phase peritoneal dissemination, a combination of 64Cu-ipRIT for down-staging and subsequent OpenPET-guided surgery for resecting large tumor masses effectively prolonged survival. OpenPET clearly detected tumors (≥3 mm in size) behind other organs in the peritoneal cavity and was useful for confirming the presence or absence of residual tumors during an operation. These findings suggest that integrated 64Cu therapy can serve as a novel treatment strategy for peritoneal dissemination.