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Lonidamine-induced, pH dependent inhibition of cellular oxygen utilization
1Edwin L. Steele Laboratory, Department of Radiation Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Abstract:
The inhibitory effect of lonidamine 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid on oxygen utilization by Chinese hamster ovary (CHO) and murine fibrosarcoma (FSa-II) cells was evaluated with a Clark oxygen electrode. The drug produced a small but statistically significant inhibition of oxygen uptake at normal pH (7.4) in CHO and FSa-II cells of 16 and 11%, respectively. However, at low pH (6.65) the inhibitory effect of lonidamine increased dramatically to 60% in both CHO and FSa-II cells. Because of the potential difference between tumor and normal tissue pH, lonidamine and similar drugs may be effective for selectively modifying oxygen utilization and concentration in tumor tissue which might lead to increased radiation and hyperthermic sensitization in tumors compared to normal tissue, resulting in an improvement in the therapeutic ratio.
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