Resistance of hypoxic cells to radiation and
chemotherapy remains a major limitation to effective
therapy of solid
tumors.
Misonidazole, a
2-nitroimidazole analogue, has been studied extensively as a radiosensitizer of hypoxic cells and has been shown to undergo bioreductive metabolism to exert preferential cytotoxicity against hypoxic cells. We have investigated the effects of
misonidazole on the biosynthesis of
prostaglandins (PGs) in a murine mammary
adenocarcinoma cell line (No. 4526) under aerobic and hypoxic conditions in attempts to exploit modulation of PG levels under
hypoxia as a means of improving therapeutic approaches for the treatment of solid
tumors. We report a time-dependent inhibition of PG biosynthesis by the suspended cells under
hypoxia induced by
flushing sealed vials with N2 (1.5 liters/min). After 30 min of
hypoxia, PG formation was inhibited by 50%.
Indomethacin was able to further inhibit the PG formation in a concentration-dependent manner under
hypoxia.
Misonidazole, however, selectively increased the
PGE2 biosynthesis under
hypoxia by 49% at 100 microM. This increase was concentration dependent over the range of 25 to 100 microM and was blocked by
indomethacin (0.1 microM).
Imidazole, the heterocyclic moiety in
misonidazole without the nitro function, had no effect on PG biosynthesis at these concentrations. These data suggest that
arachidonic acid metabolism is sensitive to the differential
oxygen levels which exist within solid
tumors and that PG levels may be modulated by electron-affinic agents in hypoxic
tumor cells.