Cytotoxic and radiosensitizing effects of misonidazole on hematopoiesis in normal and tumor-bearing mice

Abstract

Misonidazole is a 2-nitroimidazole hypoxic cell radiosensitizing agent currently undergoing clinical trials. Preliminary studies have shown that misonidazole is toxic to human hematopoietic stem cells. A survey of the effects of misonidazole on a variety of murine hematopoietic stem cells was undertaken. No cytotoxicity or radiosensitization could be demonstrated when misonidazole was administered in vivo, in assays of transplantable spleen colony cells (CFU-S), endogenous spleen colony cells and committed granulocyte-macrophage precursors (CFU-C). The ability of misonidazole to radiosensitize hypoxic CFU-S was confirmed. Misonidazole was toxic to bone marrow when incubated in vitro in liquid cultures for long periods at higher concentrations than that attainable in vivo. CFU-C proliferation was also assessed in animals bearing Lewis lung tumor. No toxicity could be demonstrated when there was a marked increase in CFU-C activity following tumor implantation or when the tumors had grown large enough to have a significant hypoxic portion. These studies indicate that misonidazole is not toxic to murine hematopoiesis in vivo, but there are indications that it may be toxic in situations in which relatively high concentrations are maintained for long periods of time.