My. Janssens et al., Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation, BR J CANC, 79(7-8), 1999, pp. 1085-1089
The radiosensitizing activity of S-nitroso-N-acetylpenicillamine (SNAP), a
nitric oxide (NO) donor, was assessed in a model of non-metabolic hypoxia a
chieved in an atmosphere of 95% nitrogen-5% carbon dioxide. A 10 min preinc
ubation of hypoxic EMT-6 cells (10 x 10(6) ml(-1)) with 0.1 and 1 mM SNAP b
efore radiation resulted in an enhancement ratio of 1.6 and 1.7 respectivel
y. The level of spontaneous NO release, measured by a NO specific microsens
or, correlated directly with the concentration of SNAP and was enhanced 50
times in the presence of cells. Dilution of the cell suspension from 10 to
0.1 x 10(6) ml(-1) resulted in a 16-fold decline in NO release, but only a
twofold decrease in radiosensitization was observed. Preincubation of hypox
ic cells with SNAP for 3 min up to 30 min caused an increasing radiosensiti
zing effect. Extended preincubation of 100 min led to the loss of radiosens
itization although the half-life of SNAP is known to be 4-5 h. Taken togeth
er, these observations suggest that SNAP generates NO predominantly by a bi
oreductive mechanism and that its biological half-life is unlikely to excee
d 30 min. The lack of correlation between free NO radical and radiosensitiz
ing activity may reflect a role of intracellular NO adducts which could con
tribute to radiosensitization as well.