Pemetrexed improves tumor selectivity of In-111-DTPA-folate in mice with folate receptor-positive ovarian cancer

CM Muller, R Schibli, Eric Krenning, Marion Jong

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Abstract

Folate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired renal retention of radioactivity. Recently, we found that the preinjection of an antifolate significantly improved tumor selectivity of organometallic Tc-99m-radiofolates in mice. The aim of this study was to corroborate the effect of pemetrexed with the clinically tested In-111-DTPA-folate (DTPA is diethylenetriaminepentaacetic acid) in a human ovarian cancer xenografted mouse model. Methods: In vivo studies were performed in female athymic nude mice bearing subcutaneous FR-positive ovarian tumors (IGROV-1 and SKOV-3) or metastases (after intraperitoneal SKOV-3 cell inoculation). Biodistribution studies were performed 1, 4, and 24 h after administration of (111) In-DTPA-folate (0.7 MBq/mouse, 0.35 mu g) with or without preinjection of pemetrexed (PMX, 400 mu g) 1 h before the radiofolate. Images were acquired with a high-resolution, high-sensitivity SPECT/CT camera, 4 and 24 h after injection of the radiotracer (30-50 MBq/ mouse, 4.5-10 mu g). Results: In biodistribution studies the tumor uptake of In-111-DTPA-folate (IGROV-1: 9.79 +/- 3.21 %ID/g [percentage injected dose per gram]; SKOV-3: 7.57 +/- 0.61 %ID/g, 4 In after injection) was high and retained over the time of investigation. However, considerable retention of radioactivity was found in kidneys (85-105 %ID/g, 4 h after injection), resulting in unfavorably low tumor-to-kidney ratios (similar to 0.10). Preinjection of PMX resulted in a significant reduction of renal uptake (20%-30% of control values, P < 0.03) at all time points after injection of In-111-DTPA-folate, whereas the tumor uptake was retained Thus, the tumor-to-kidney ratio was significantly increased to similar to 0.50. SPECT/CT images confirmed the superior tumor-to-background ratio in mice injected with PMX These findings were particularly evident in mice with SKOV-3 metastases that could be visualized only when In-111-DTPA-folate was administered in combination with PMX Conclusion: The application of PMX resulted in a significant reduction of undesired radioactivity accumulation in kidneys, whereas the tumor uptake remained unaffected. These observations suggest a general validity of the reducing effect of PMX on the uptake of radiofolates in kidneys. Our findings will lead the way toward the development of folate-based radiotherapy.
Original languageUndefined/Unknown
Pages (from-to)623-629
Number of pages7
JournalJournal of Nuclear Medicine
Volume49
Issue number4
DOIs
Publication statusPublished - 2008

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