title: 177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.
abstract: Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity.
authors.affiliation: Corresponding Author: Cristina Müller, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland. cristina.mueller@psi.ch.
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haller
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D056831:Coordination Complexes / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000037:antagonists & inhibitors*; D005492:Folic Acid / Q000627:therapeutic use*; D005493:Folic Acid Antagonists / Q000008:administration & dosage*; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007624:KB Cells; D008187:Lutetium / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy*; D000068437:Pemetrexed; D010865:Pilot Projects; D011868:Radioisotopes / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000589258:177Lu-EC0800; D056831:Coordination Complexes; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D005971:Glutamates; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D000068437:Pemetrexed; D008187:Lutetium; D006147:Guanine; D005492:Folic Acid