Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer.

BACKGROUND: Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. METHODS: 99mTc-MIBI and 99mTc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. RESULTS: In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized, whereas 99mTc-TF had high stability. CONCLUSION: 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

Formal Synthesis of Dictyodendrin B.

A formal synthesis of dictyodendrin B is described. Regiocontrolled functionalization of the α,ß-dibromopyrrole derivative provided the fully substituted pyrrole bearing an indole moiety. Subsequent reductive cyclization using a combination of sodium dispersion and triethylsilyl chloride enabled the formation of the benzene ring in the characteristic tetracyclic pyrrolo[2,3-c]carbazole skeleton, while the ethyl ester remained untouched. Further chemical transformation of the ester moiety and functional group manipulation completed the formal synthesis of dictyodendrin B.

A strategy for improving FDG accumulation for early detection of metastasis from primary pancreatic cancer: stimulation of the Warburg effect in AsPC-1 cells.

INTRODUCTION: Early detection and/or prediction of metastasis provide more prognostic relevance than local recurrence. Direct spread into the peritoneum is frequently found in pancreatic cancer patients, but positron emission tomography (PET) with 2-deoxy-2-fluoro-d-glucose (FDG) is not useful for identifying such metastasis. We investigated a method to enhance FDG accumulation using AsPC-1 human ascites tumor cells. METHODS: (14)C-FDG accumulation was assessed under the following conditions: 1) characteristics of (14)C-FDG transport were examined using phloridzin, a Na(+)-free buffer, and various hexoses, and 2) accumulation of (14)C-FDG was measured in cells that were pretreated with hexose for various time periods, and activity of 6-phosphofructo-1-kinase (PFK-1) was assayed. RESULTS: (14)C-FDG transport into AsPC-1 cells was mediated primarily by a Na(+)-independent transport mechanism. Aldohexoses such as d-glucose, D-mannose, and D-galactose inhibited (14)C-FDG transport. Cells pretreated with d-glucose, D-mannose, or D-fructose exhibited augmented (14)C-FDG accumulation. Pretreatment with higher concentrations of D-glucose or D-fructose tended to increase PFK-1 activity. CONCLUSIONS: Very little information has been published about the association between PFK-1 and FDG accumulation, and we confirmed the impacts of various hexoses on the activity of PFK-1 and FDG accumulation in AsPC-1 cells. Clarifying the relevance of PFK-1 in FDG accumulation will contribute to developing new features of FDG-PET, because PFK-1 is the main regulator of glycolysis.