TY - JOUR T1 - Effects of Antifolate Drugs on the Cellular Uptake of Radiofolates In Vitro and In Vivo JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 2057 LP - 2064 VL - 47 IS - 12 AU - Cristina Müller AU - Matthias Brühlmeier AU - P. August Schubiger AU - Roger Schibli Y1 - 2006/12/01 UR - http://jnm.snmjournals.org/content/47/12/2057.abstract N2 - Targeting the folate receptor (α-FR) with radiolabeled folates for the noninvasive diagnosis and therapy of α-FR–overexpressing neoplastic tissue is of great interest. However, the tumor uptake of folate-based radiotracers was shown to be low compared with the high renal retention of radioactivity attributable to α-FR expression in the proximal tubule cells. In order to increase the tumor uptake of radiofolates, we wanted to stimulate α-FR expression or transport through coapplication of the antifolates methotrexate (MTX), raltitrexed (RTX), and pemetrexed (PMX). Methods: 99mTc-picolylamine monoacetic acid folate (99mTc-PAMA-folate) was used for these studies. The in vitro experiments with antifolates were performed with α-FR–positive KB cancer cells. In vivo experiments were performed with KB tumor–bearing athymic nude mice. In vivo images were acquired with a small-animal SPECT/CT scanner. Results: KB cells incubated with solutions (10 μmol/L) of MTX, RTX, or PMX for 24 h displayed twice as much 99mTc-PAMA-folate uptake as untreated cells. In contrast, KB tumor–bearing mice that received MTX intravenously 24 h before 99mTc-PAMA-folate showed significantly lower uptake of the radiofolate in tumors (1.35 ± 0.33 percentage injected dose per gram of tissue [%ID/g] [mean ± SD]) and the α-FR–positive kidneys (9.35 ± 1.73 %ID/g) than did control mice (2.33 ± 0.36 and 18.48 ± 0.72 %ID/g, respectively, at 4 h after injection). When the antifolate PMX and 99mTc-PAMA-folate were injected 1 h apart, the tumor uptake of the radiotracer was unaffected (2.21 ± 0.34 %ID/g at 4 h after injection), whereas radioactivity in the kidneys was significantly decreased (1.14 ± 0.18 %ID/g at 4 h after injection). In vivo SPECT/CT studies demonstrated the specific accumulation of 99mTc-PAMA-folate in tumors and almost a complete absence of radioactivity in the renal tissue of mice preinjected with PMX. Conclusion: Our data suggest that the preadministration of antifolates improves tumor-to-kidney ratios of radiofolates and opens a “therapeutic window” for folates radiolabeled with particle-emitting nuclides, which could otherwise be nephrotoxic. ER -