PMID- 17138750 OWN - NLM STAT- MEDLINE DCOM- 20070305 LR - 20161124 IS - 0161-5505 (Print) IS - 0161-5505 (Linking) VI - 47 IP - 12 DP - 2006 Dec TI - Effects of antifolate drugs on the cellular uptake of radiofolates in vitro and in vivo. PG - 2057-64 AB - Targeting the folate receptor (alpha-FR) with radiolabeled folates for the noninvasive diagnosis and therapy of alpha-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 alpha-FR expression in the proximal tubule cells. In order to increase the tumor uptake of radiofolates, we wanted to stimulate alpha-FR expression or transport through coapplication of the antifolates methotrexate (MTX), raltitrexed (RTX), and pemetrexed (PMX). METHODS: (99m)Tc-picolylamine monoacetic acid folate ((99m)Tc-PAMA-folate) was used for these studies. The in vitro experiments with antifolates were performed with alpha-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 micro mol/L) of MTX, RTX, or PMX for 24 h displayed twice as much (99m)Tc-PAMA-folate uptake as untreated cells. In contrast, KB tumor-bearing mice that received MTX intravenously 24 h before (99m)Tc-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 alpha-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 (99m)Tc-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 (99m)Tc-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. FAU - Muller, Cristina AU - Muller C AD - Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland. FAU - Bruhlmeier, Matthias AU - Bruhlmeier M FAU - Schubiger, P August AU - Schubiger PA FAU - Schibli, Roger AU - Schibli R LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Nucl Med JT - Journal of nuclear medicine : official publication, Society of Nuclear Medicine JID - 0217410 RN - 0 (Folic Acid Antagonists) RN - 0 (Organotechnetium Compounds) RN - 0 (Radiopharmaceuticals) RN - 0 (technetium 99m picolylamine monoacetic acid folate) RN - 935E97BOY8 (Folic Acid) SB - IM MH - Animals MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Female MH - Folic Acid/*analogs & derivatives/pharmacokinetics MH - Folic Acid Antagonists/*administration & dosage MH - Humans MH - Metabolic Clearance Rate/drug effects MH - Mice MH - Mice, Nude MH - Nasopharyngeal Neoplasms/*diagnostic imaging/*metabolism MH - Organ Specificity/drug effects MH - Organotechnetium Compounds/*pharmacokinetics MH - Radionuclide Imaging MH - Radiopharmaceuticals/pharmacokinetics MH - Tissue Distribution/drug effects EDAT- 2006/12/02 09:00 MHDA- 2007/03/06 09:00 CRDT- 2006/12/02 09:00 PHST- 2006/12/02 09:00 [pubmed] PHST- 2007/03/06 09:00 [medline] PHST- 2006/12/02 09:00 [entrez] AID - 47/12/2057 [pii] PST - ppublish SO - J Nucl Med. 2006 Dec;47(12):2057-64.