Ascorbate-enhanced Cytotoxicity of misonidazole

Abstract

MISONIDAZOLE, an electron-affinic, nitroheterocyclic compound (1-(2-nitro-1-imidazole)-3 methoxy-2-propanol, Ro-07-0582) is undergoing preliminary clinical trials, which are exploring its capacity to sensitise hypoxic tumour cells to ionising radiation damage^1–4. The drug also possesses a substantial cytotoxic effect, independent of radiation, which is selectively expressed in hypoxic cells^5,6. Both of these properties may contribute to the potential value of this agent as an adjunct to radiation therapy of malignant disease in those situations where radioresistant hypoxic cells represent the limiting factor in achieving local control. It is also possible that the cytotoxic property could be a useful adjunct to chemotherapy as it should be effective against noncycling hypoxic tumour cells. Misonidazole, however, may be cytotoxic to the normal hypoxic tissues in the human body (nerve, skin, cartilage, and so on) and this is a major concern in the clinical application of the drug^1,4. Furthermore, misonidazole is metabolised in mammalian cells and at least two products have been isolated⁷, toxic to both aerobic and hypoxic mammalian cells. Thus, if they are able to diffuse freely, the metabolites may also be a threat to aerobic tissues⁸. This Cytotoxicity of misonidazole is temperature dependent^5,9,10, and varies with cell line^11,12, and cysteamine seems to protect against it¹³. It leads to strand breaks in cellular DNA and those cells which fail to survive also fail to repair these strand breaks¹². In this work we show the effect of ascorbic acid (vitamin C) on the cytotoxicity of misonidazole.