1: Clin Cancer Res. 2008 May 1;14(9):2768-2774.

The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into
Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy.

Frérart F, Sonveaux P, Rath G, Smoos A, Meqor A, Charlier N, Jordan BF, Saliez J,
Noël A, Dessy C, Gallez B, Feron O.

Authors' Affiliations: Unit of Pharmacology and Therapeutics, Université
catholique de Louvain, UCL-FATH and Biomedical Magnetic Resonance, Université
catholique de Louvain, UCL-REMA, Brussels, Belgium; and Laboratory of Tumor and
Developmental Biology, University of Liège, Tour de Pathologie (B23),
Sart-Tilman, Belgium.

PURPOSE: The biological status of nitrite recently evolved from an inactive end
product of nitric oxide catabolism to the largest intravascular and tissue
storage of nitric oxide (NO). Although low partial O(2) pressure favors enzymatic
reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because 
hypoxia and acidity are characteristics of the tumor microenvironment, we
examined whether nitrite injection could preferentially lead to NO production in 
tumors and influence response to treatments. EXPERIMENTAL DESIGN: The effects of 
nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and
tumor blood flow, oxygenation, and response to radiotherapy. RESULTS: We first
showed that a small drop in pH (-0.6 pH unit) favored the production of bioactive
NO from nitrite by documenting a higher cyclic guanosine
3',5'-monophosphate-dependent arteriole vasorelaxation. We then documented that
an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient
increase in partial O(2) pressure in tumor but not in healthy tissues. Blood flow
measurements failed to reveal an effect of nitrite on tumor perfusion, but we
found that O(2) consumption by nitrite-exposed tumor cells was decreased at
acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to 
radiotherapy, leading to a significant growth delay and an increase in mouse
survival (versus irradiation alone). CONCLUSIONS: This study identified low pH
condition (encountered in many tumors) as an exquisite environment that favors
tumor-selective production of NO in response to nitrite systemic injection. This 
work opens new perspectives for the use of nitrite as a safe and clinically
applicable radiosensitizing modality.


PMID: 18451244 [PubMed - as supplied by publisher]

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