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

Abstract

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.

Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use

“…CA IX also contributes to therapy resistance, because tumors expressing high CA IX levels are less responsive to experimental therapy, and inhibition of CA IX catalytic activity significantly improves their chemo-or radiosensitivity [79,80]. Similarly, CA IX inhibition can enhance the effect of anti-angiogenic therapy with anti-VEGF antibody [64].…”

“…Last, but not least, a very interesting design was adopted in development of dual targeting bioreductive nitroimidazole-based anti-CA IX sulfamide drug (DH348), which was shown to reduce tumor growth in mice and sensitize tumors to irradiation in a CA IX-dependent manner [80]. This dual-activity compound appears more promising than the single activity CA inhibitors due to combination of hypoxia-related selectivity/activation typical for the bioreductive drugs and binding to CA IX, which is present on the surface of the hypoxic cells.…”

Carbonic Anhydrase Ix Inhibitors in Cancer Therapy: An Update

“…All these compounds showed efficacy in vitro for the inhibition of hypoxic cellular tumor acidification in two cell lines overexpressing CA IX (colorectal carcinoma cell line HT-29 and cervical carcinoma cell line HeLa). The lead molecule 13 (Figure 4) was demonstrated to slow down tumor growth at nontoxic dose and to enhance sensitization toward radiotherapy in a CA IX dependent manner [36]. Moreover, 13 was shown to sensitize tumors toward doxorubicin-based chemotherapy in vivo, the sensitization effects being markedly higher compared with single CA IX targeting agent [33].…”

Technical innovation in adjuvant radiotherapy: Evolution and evaluation of new treatments for today and tomorrow

“…The tail present in the sulphonamide CA inhibitors is essential for binding of the inhibitor within the active site. One of a novel sulfamate class of CAIX inhibitors has been shown to reduce the spread, proliferation and migration of human MBA-MB-231 breast cancer cells [68,72,73] and several recent studies have demonstrated the potential of these novel inhibitors to enhance the in vitro and in vivo effectiveness of radiotherapy using a colorectal cancer model [74,75]. Investigations in our laboratory suggest that these inhibitors may also increase the effects of radiation in several breast cancer models (unpublished data).…”