The Mechanisms of Cytotoxicity and Chemosensitization by Misonidazole and Other Nitroimidazoles

This paper attempts to review and interpret the various aspects of the interaction of the electron-affinic drug misonidazole (MISO) with cells in vitro and tumors in vivo. Specifically three topics are covered: (1) The preferential toxicity of MISO to hypoxic cells; (2) The sensitization of cells in vitro in chemotherapeutic agents by hypoxic pretreatment with MISO (the "preincubation effect"); (3) The chemosensitization of tumors in vivo by MISO. It is concluded that hypoxic cell cytotoxicity is not a result of the binding of nitroreduction products to the cellular target molecule (or molecules), but is a result of abstraction of H atoms by neutral radicals produced during nitroreduction. However, binding does occur, and this depletes intracellular glutathione which is capable both of inactivating these toxic radicals and repairing the target lesions. The preincubation effect--at least for bifunctional alkylating agents--is postulated to be a result of a combination of depletion of intracellular glutathione (which can "intercept" the alkylating agent), and increase in DNA interstrand cross-links. Finally, it is concluded that chemosensitization of tumors in vivo is a combination of the in vitro preincubation effect for the hypoxic cells, and an inhibition of repair of the chemotherapeutic agent damage to aerated, plateau-phase-like cells in the tumor. The former required nitroreduction, the latter does not.