Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Radiother Oncol. 2013 Sep;108(3):523-8. doi: 10.1016/j.radonc.2013.06.018. Epub 2013 Jul 9.

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

Author information

  • 1Dept. of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands. Electronic address: ludwig.dubois@maastrichtuniversity.nl.

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 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.

Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

KEYWORDS:

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

PMID:
23849171
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Write to the Help Desk