Abstract
Expression of multidrug pumps including P-glycoprotein (MDR1, ABCB1) in the plasma membrane of tumor cells often results in decreased intracellular accumulation of anticancer drugs causing serious impediment to successful chemotherapy. It has been shown earlier that combined treatment with UIC2 anti-Pgp monoclonal antibody (mAb) and cyclosporine A (CSA) is an effective way of blocking Pgp function. In the present work we investigated the suitability of four PET tumor diagnostic radiotracers including 2-[18F]fluoro-2-deoxy-D-glucose (18FDG), 11C-methionine, 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT), and [18F]fluoroazomycin-arabinofuranoside (18FAZA) for in vivo follow-up of the efficacy of chemotherapy in both Pgp positive (Pgp+) and negative (Pgp−) human tumor xenograft pairs raised in CB-17 SCID mice. Pgp+ and Pgp− A2780AD/A2780 human ovarian carcinoma and KB-V1/KB-3-1 human epidermoid adenocarcinoma tumor xenografts were used to study the effect of the treatment with an anticancer drug doxorubicin combined with UIC2 and CSA. The combined treatment resulted in a significant decrease of both the tumor size and the accumulation of the tumor diagnostic tracers in the Pgp+ tumors. Our results demonstrate that 18FDG, 18F-FLT, 18FAZA, and 11C-methionine are suitable PET tracers for the diagnosis and in vivo follow-up of the efficacy of tumor chemotherapy in both Pgp+ and Pgp− human tumor xenografts by miniPET.
Highlights
The miniPET technique is a well-established noninvasive method to detect tumors and follow up the effect of therapy of tumors, using PET tumor diagnostic tracers
The PET tumor diagnostic tracers, like 11C-metionine, 2-[18F]fluoro2-deoxy-D-glucose (18FDG), and (3-deoxy-3-[18F]fluorothymidine) (18F-FLT), are good candidates to measure the effect of the therapy. 18FDG, an analog of glucose, the most commonly used PET radiotracer in clinical oncology, allows visualization of the changes in the glucose metabolic rate in tumors [1,2,3]. 18FDG undergoes phosphorylation by hexokinase but can not pass through the rest of glycolysis, and it remains trapped in the cell
The KB-V-1 cells were cultured in the presence of 180 nM vinblastine and the A2780AD cells were cultured with 2 μM doxorubicin until use
Summary
The miniPET technique is a well-established noninvasive method to detect tumors and follow up the effect of therapy of tumors, using PET tumor diagnostic tracers. BioMed Research International (TK1) in the S phase of cell cycle [4, 5] Another tumor diagnostic PET tracer is the 11C labelled methionine applied for the follow-up of the amino acid transport and metabolism in the tumor [6]. The conformation sensitive UIC2 mouse monoclonal antibody inhibits Pgp mediated substrate transport This inhibition is usually partial and its extent is variable, since UIC2 binds only to 10–40% of all Pgp molecules present in the cell membrane [10, 11]. Krasznai et al [12] demonstrated that the combined treatment with UIC2 antibody and Pgp modulators effectively blocked the function of Pgp in ovarian carcinoma cells in vitro and the effect could be followed by using tumor diagnostic tracers, 99mTc-MIBI and 18FDG. In this paper using an animal model we demonstrate that the miniPET technique combined with tumor diagnostic radiopharmaceuticals is suitable for the detection of either Pgp expressing or Pgp nonexpressing tumors and it can be applied for in vivo monitoring of the effect of tumor therapy
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