Effects of the antifolates pemetrexed and CB3717 on the tissue distribution of (99m)Tc-EC20 in xenografted and syngeneic tumor-bearing mice.
Administration of certain antifolates before radiofolate application has previously proven to have a positive effect on undesired kidney uptake of radiofolates in mice bearing human tumor xenografts. The aims of this study were to (i) test the effects of the antifolates, pemetrexed and CB3717, on tissue distribution of the clinically investigated radiofolate, (99m)Tc-EC20, and (ii) to determine if pemetrexed's kidney-selective blocking effect also functions in mice bearing syngeneic tumors. Relative binding affinities of pemetrexed and CB3717 were determined in folate receptor (FR)-positive KB cells at 0 and 37 degrees C using (3)H-folic acid. In vivo studies were performed in nude mice with KB tumor xenografts (A) and in Balb/c mice bearing FR-positive M109 tumor grafts (B). (99m)Tc-EC20 was prepared via a kit formulation. The antifolates pemetrexed and CB3717 (20 mumol/kg body weight) were administered intravenously 1 h before injection of (99m)Tc-EC20 (67 nmol/kg body weight). Similar to previously published data we found that FR-binding affinities of pemetrexed and CB3717 at 0 degrees C were in the same range as that of folic acid. Interestingly, experiments performed at 37 degrees C showed that pemetrexed has a nearly approximately 700-fold lower FR-affinity than CB3717. Tissue distribution of (99m)Tc-EC20 was largely comparable in both animal models (A and B). Radiofolate accumulation was found in FR-positive tumors (A, 8.92 +/- 2.14% ID/g; B, 15.02 +/- 0.95% ID/g) and FR-positive kidneys (A, 59.10 +/- 8.03% ID/g; B, 69.44 +/- 4.66% ID/g, 4 h p.i.). Preinjection of pemetrexed resulted in a significant decrease of (99m)Tc-EC20 uptake in kidney (A, 18.80 +/- 2.73% ID/g; B, 15.27 +/- 2.64% ID/g; 4 h p.i), whereas uptake in the tumors was unaltered. However, administration of the CB3717 resulted in a reduction of (99m)Tc-EC20 uptake in both the kidney and tumor (<1% ID/g, 4 h p.i.). We have thus demonstrated that pemetrexed effectively reduces kidney uptake of radiofolates not only in xenografted mice but also in a syngeneic tumor mouse model, thereby indicating that the kidney-specific blocking effect is not based on differences between human and murine FRs that are expressed in xenografts and kidneys, respectively. This effect was not observed with the antifolate, CB3717, which targets the FR selectively in contrast to pemetrexed that is predominantly transported into cells through carrier systems.
Müller
Cristina
C
Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.
Reddy
Joseph A
JA
Leamon
Christopher P
CP
Schibli
Roger
R
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000737:chemistry; D000068437:Pemetrexed; D011799:Quinazolines / Q000494:pharmacology*; D013667:Technetium / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
C473829:EC20 folate peptide; D005493:Folic Acid Antagonists; D005971:Glutamates; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D013667:Technetium; C031662:CB 3717; D005492:Folic Acid