SR-4233 (
Tirapazamine) is a hypoxic cell selective
cytotoxic agent currently in Phase I clinical trial. Although
SR-4233 is selectively cytotoxic toward hypoxic cells some cytotoxicity toward normally oxygenated cells also occurs.
SR-4233 (500 microM, 1 h) killed about 70% of normally oxygenated and 99% of hypoxic human MCF-7
breast carcinoma cells. Using a polarographic chamber and a Clark O2
electrode the O2 consumption of MCF-7 cells was measured in the presence or absence of
SR-4233 (500 microM) or other inhibitors or uncouplers of oxidative phosphorylation. MCF-7 cells exhibited increased O2 consumption in the presence of
SR-4233 alone and
after treatment with
oligomycin but not
after treatment with retenone. The pattern of O2 consumption observed
after treatment with
SR-4233 was very similar to that seen when the cells were treated with the classical uncoupler
FCCP. After 1 h of exposure to
SR-4233 (500 microM) the cells were not responsive to treatment with
oligomycin or
FCCP for at least 3 h, but by 24 h post exposure to
SR-4233 the cells had regained responsiveness to both
FCCP and
oligomycin. These results indicate that in normally oxygenated cells
SR-4233 acts as an uncoupler of oxidative phosphorylation so that the cells continue to consume O2 but no
ATP is produced. This condition can lead to
ATP depletion especially in respiration intensive tissues and may provide an explanation for the muscle cramping observed in some patients treated with
SR-4233.