Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs
| Autor: | Marc Vooijs, Claudiu T. Supuran, Jean-Yves Winum, Ruchi Saraya, Nanda Kumar Parvathaneni, Marouan Rami, Simon J. A. van Kuijk, Daniela Vullo, R. Biemans, Ala Yaromina, Philippe Lambin, S. Peeters, Natasja G. Lieuwes, Ludwig Dubois |
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| Přispěvatelé: | RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Radiotherapie, Ondersteunend personeel ODB, MUMC+: MA Radiotherapie OC (9), RS: GROW - School for Oncology and Reproduction |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Drug
Radiation-Sensitizing Agents media_common.quotation_subject Dual targeting Metastasis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo Antigens Neoplasm Cell Line Tumor Extracellular medicine Animals Humans Radiology Nuclear Medicine and imaging Radiosensitivity Carbonic Anhydrase IX Carbonic Anhydrase Inhibitors Carbonic anhydrase IX (CAIX) Sulfamide 030304 developmental biology media_common Carbonic Anhydrases 0303 health sciences Nitroimidazole Radiotherapy Hematology medicine.disease In vitro 3. Good health chemistry Oncology Nitroimidazoles Radiology Nuclear Medicine and imaging 5-Nitroimidazole 030220 oncology & carcinogenesis Cancer research Colorectal Neoplasms |
| Zdroj: | Radiotherapy and Oncology; Vol 108 Radiotherapy and Oncology, 108(3), 523-528. Elsevier Ireland Ltd Radiotherapy and Oncology |
| ISSN: | 1879-0887 0167-8140 |
| DOI: | 10.1016/j.radonc.2013.06.018 |
| Popis: | Background and purpose Carbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner. Material and methods The effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10 mg/kg) combined with tumor single dose irradiation (10 Gy). Results In vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors. Conclusions A newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no “off-target” effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting. |
| Databáze: | OpenAIRE |
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