- 作者：Ludwig Dubois ; Sarah G.J.A. Peeters ; Simon J.A. van Kuijk ; Ala Yaromina ; Natasja G. Lieuwes ; Ruchi Saraya ; Rianne Biemans ; Marouan Rami ; N ; a Kumar Parvathaneni ; Daniela Vullo ; Marc Vooijs ; Claudiu T. Supuran ; Jean-Yves Winum ; Philippe Lambin
- 关键词：Carbonic anhydrase IX (CAIX) ; Dual targeting ; Sulfamide ; 5-Nitroimidazole ; Radiotherapy
- 刊名：Radiotherapy and Oncology
- 出版年：September, 2013
- 年：2013
- 卷：108
- 期：3
- 页码：523-528
- 全文大小：1721 K
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脳 start volume (T4脳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 鈥渙ff-target鈥?effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting.