journal contribution
posted on 2023-04-03, 13:46 authored by Josefine Reber, Stephanie Haller, Christopher P. Leamon, Cristina Müller <p>PDF - 569KB, Figure S1: Chemical structures of the compounds applied in this study. Figure S2: Results of the internalization studies of 177Lu-EC0800 performed with FR-positive and FR-negative tumor cell lines Figure S3: Results of a clonogenic assay performed with 177Lu-EC0800 with/without co-application of folic acid using KB and IGROV-1 tumor cells Figure S4: Representation of the area under the curve (AUC) necessary to determine the absorbed dose to the tumors and kidneys. Figure S5: Results of the biodistribution data obtained in KB tumor bearing nude mice injected with 3H-pemetrexed Figure S6: Graphs representing the body weight and survival of mice treated with pemetrexed compared to untreated control mice. Figure S7: Distribution of the cell fractions in a particular cell cycle phase after treatment with 177Lu-EC0800, PMX or both of these agents. Figure S8: Graphs representing the apoptotic fraction of KB and IGROV-1 cells after treatment with 177Lu-EC0800, PMX or both of these agents.</p>
History
ARTICLE 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. PMXsubther protected the kidneys from undesired side effects of 177Lu-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. ©2013 AACR.
