期刊
RADIOTHERAPY AND ONCOLOGY
卷 108, 期 3, 页码 523-528出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2013.06.018
关键词
Carbonic anhydrase IX (CAIX); Dual targeting; Sulfamide; 5-Nitroimidazole; Radiotherapy
资金
- Maastro Cancer Foundation [KWF UM2012-5394]
- EU [2008-222741]
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 4x start volume (T4xSV) 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. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved.
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