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Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

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Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy Published OnlineFirst September 12, 2013; DOI: 10.1158/1535-7163.MCT-13-0422-T Molecular Cancer Small Molecule Therapeutics Therapeutics 177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy Josefine Reber1, Stephanie Haller1, Christopher P. Leamon2, and Cristina Muller€ 1 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 177Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of 177Lu-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 177Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of 177Lu-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. 177 PMXsubther protected the kidneys from undesired side effects of 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 99mTc-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. Mol Cancer Ther; 12(11); 2436–45. Ó2013 AACR. Introduction The development of new targeting strategies for the Targeted radionuclide therapy has shown impressive treatment of further tumor types is of high interest and results for the palliative treatment of several cancer dis- would have a critical impact on the future management of eases. It is based on the use of particle-emitting radio- these cancer diseases. In this respect, the folate receptor is isotopes (e.g., 177Lu, 90Y, 131I) in conjunction with tumor- an attractive target as it has been identified as specifically targeted biomolecules (e.g., peptides, antibodies; ref. 1). A associated with a variety of cancer types, such as ovarian, prominent example of a successfully used radiopharma- endometrial, lung, brain, breast, and colorectal cancer (4, ceutical in clinical routine are somatostatin-based radio- 5). The vitamin folic acid has been used as a targeting peptides (e.g., 177Lu-DOTATATE, 90Y-DOTATOC) for ligand because it binds to the folate receptor with high the treatment of neuroendocrine tumors (2). Moreover, affinity followed by endocytotic internalization of the radiolabeled antibodies such as 90Y-Ibritumomab (Zeva- therapeutic payload into cancer cells (6). While folic acid lin) and 131I-tositumomab (Bexxar) are approved for the conjugates of highly toxic chemotherapeutics have been treatment of non-Hodgkins lymphoma (3). successfully used in clinical trials (7, 8), application of therapeutic folic acid radioconjugates is currently being developed in preclinical studies. Substantial expression of the folate receptor in the Authors' Affiliations: 1Center for Radiopharmaceutical Sciences ETH- proximal tubule cells of the kidneys results in commonly PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland; 2Endocyte Inc., West Lafayette, Indiana high and specific renal uptake of folate-based radio- conjugates (9, 10). As a consequence there is an inherent Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). risk of damage to the kidneys by particle radiation. How- ever, we have shown in several preclinical studies that Corresponding Author: Cristina Muller,€ Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzer- administration of the antifolate pemetrexed (PMX) re- land. Phone: 41-56-310-44-54; Fax: 41-56-310-28-49; E-mail: sulted in a tremendous reduction of the radiofolate’s [email protected] retention in the kidneys whereas accumulation in tumor doi: 10.1158/1535-7163.MCT-13-0422-T xenografts remained unaffected (11–13). The exact mech- Ó2013 American Association for Cancer Research. anism of this interaction is still not completely clear. 2436 Mol Cancer Ther; 12(11) November 2013 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst September 12, 2013; DOI: 10.1158/1535-7163.MCT-13-0422-T 177Lu-Folate Therapy in Combination with Pemetrexed However, in numerous preclinical studies, we observed organisms and Cell Cultures (DSMZ). IGROV-1 cells an interrelation between the kidney reducing effect and (human ovarian carcinoma cells) were a kind gift from the time point of preinjected PMX (14) as well as the molar Dr. Gerrit Jansen (Department of Rheumatology, VU amount of PMX and the folate radioconjugate, respective- University Medical Center, Amsterdam, the Nether- ly (15). However, the reduced kidney uptake of radio- lands). All 3 cell lines were authenticated by DMSZ based folates was not a result of PMX’s antifolate activity as the on DNA profiling. KB and IGROV-1 cells are known to effect was maintained even if PMX was applied in com- express the folate receptor (31, 32), whereas folate receptor bination with the antidote thymidine (16). These facts negative PC-3 cells (33) were used as a negative control. suggest that PMX’s kidney reducing effect is based on a PC-3 cells were cultured in RPMI 1640 medium (Amimed) competition among PMX and the folate radioconjugate for whereas KB and IGROV-1 cells were cultured in folate- folate receptor binding sites in the kidneys. free RPMI medium referred to as FFRPMI (without folic PMX is a multitargeted antifolate, which is clinically acid, vitamin B12, and phenol red; Cell Culture Technol- approved for the treatment of pleural mesothelioma ogies GmbH). Cell culture media were supplemented and non–small cell lung cancer in combination with with 10% fetal calf serum, L-glutamine, and antibiotics cisplatin (17–19). Moreover, PMX is currently being (penicillin/streptomycin/fungizone). Routine culture tested in a number of clinical trials for the treatment treatment was conducted twice a week. Uptake and inter- of several other cancer types (reviewed in ref. 20), nalization studies of 177Lu-EC0800 as well as clonogenic among those is also ovarian cancer (21). PMX has and MTT assays were conducted as previously reported been used in combinations with gemcitabine, tyrosine in the literature in detail in the Supplementary Methods kinase inhibitors, antibodies, or even external radiation (29, 34). (22–24). A combination of PMX with external radiother- apy was based on the observation that PMX acts as a MTT assay radiosensitizing agent in variable types of cancer cells Cell viability was assessed using an MTT assay (35). In in vitro and in vivo (25–28). brief, KB, IGROV-1, and PC-3 cells were treated with We hypothesized that PMX would have a dual role if it 200 mL FFRPMI medium (without supplements) contain- was combined with therapeutic folate radioconjugates. ing 177Lu-EC0800 (0.001–5.0 MBq/mL) and/or PMX First, it was expected to prevent radionephropathy by (0.01–100 mmol/L; pemetrexed, Alimta, LY231514; Eli reducing the absorbed radiation dose of folate radio- Lilly, Supplementary Fig. S1). The control cells were conjugates in the kidneys. Second, PMX was believed to incubated with FFRPMI medium only. After 4 hours enhance the therapeutic efficacy of folate-based radio- incubation at 37C, the cells were washed once with nuclide tumor therapy by its action as a chemotherapeutic 200 mL PBS followed by addition of FFRPMI or RPMI and radiosensitizing agent. medium (with supplements). Cells were then allowed to The goal of this study was to show the anticipated dual grow for 4 days at 37C without changing medium. role of PMX. For this purpose, we used an established Analysis of the viability was conducted as previously DOTA-folate conjugate (EC0800; ref. 29), which was reported using an MTT reagent and a microplate reader 177 T ¼ E radiolabeled with Lu ( 1/2 6.7 days, av(b-): 134 keV, (Victor X3; Perkin Elmer; ref. 36). To quantify cell viability, E 177 (g): 113 keV, 208 keV). Lu-EC0800 was applied in the absorbance of the test samples was expressed as combination with PMX using 2 folate receptor positive percentage of the absorbance of the control cell samples human cancer cells (KB and IGROV-1) in vitro and as (¼100%). Dose–response curves were analyzed using the human tumor xenografts in athymic nude mice. More- software GraphPad Prism (version 4.0). Inhibition of cell over, the protective effect of PMX on the kidneys to reduce viability was expressed as the half-maximal inhibitory the absorbed radiation dose was investigated in non– concentration of PMX (IC50 in mmol/L) and as the half- tumor-bearing mice. maximal inhibitory activity concentration of 177Lu- EC0800 (IAC50 in MBq/mL) by measuring dose–response Materials and Methods curves of PMX and 177Lu-EC0800. The dose–response Preparation of 177Lu-EC0800 curves were used to determine the combination index The DOTA-folate conjugate (EC0800; ref. 29) was kindly (CI) according to Chou and colleagues (Supplementary provided by Endocyte Inc. (Supplementary Fig. S1). The Methods; ref. 37). radiosynthesis of 177Lu-EC0800 and the evaluation of its stability were carried out as previously reported (Supple- Animal studies 177 in vivo mentary Methods; ref.
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