title: Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys.
abstract: BACKGROUND
  The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF).
  
  
  METHODS
  Biodistribution was assessed 4 h postinjection of the organometallic (99m)Tc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50-400 microg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5-50 microg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g).
  
  
  RESULTS
  PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%+/-0.40% ID/g vs. control: 1.79%+/-0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 microg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g).
  
  
  CONCLUSIONS
  Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF.
authors: Department of Nuclear Medicine, Erasmus MC, 3015 CE Rotterdam, The Netherlands. c.muller@erasmusmc.nl
authors: Cristina
authors: C
authors: Müller
authors: Roger
authors: R
authors: Schibli
authors: Flavio
authors: F
authors: Forrer
authors: Eric P
authors: EP
authors: Krenning
authors: Marion
authors: M
authors: de Jong
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013763:Tetrahydrofolates / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D005493:Folic Acid Antagonists; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013763:Tetrahydrofolates; C517544:technetium 99m picolylamine monoacetic acid folate; D005492:Folic Acid; C005984:5-methyltetrahydrofolate