Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs

Ludwig Dubois*, Sarah G. J. A. Peeters, Simon J. A. van Kuijk, Ala Yaromina, Natasja G. Lieuwes, Ruchi Saraya, Rianne Biemans, Marouan Rami, Nanda Kumar Parvathaneni, Daniela Vullo, Marc Vooijs, Claudiu T. Supuran, Jean-Yves Winum, Philippe Lambin

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

63 Citations (Web of Science)

Abstract

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.
Original languageEnglish
Pages (from-to)523-528
JournalRadiotherapy and Oncology
Volume108
Issue number3
DOIs
Publication statusPublished - Sep 2013

Keywords

  • Carbonic anhydrase IX (CAIX)
  • Dual targeting
  • Sulfamide
  • 5-Nitroimidazole
  • Radiotherapy

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