Chemosensitization of Mouse Tumors by Misonidazole

The chemosensitizing action of misonidazole when used in combination with chemotherapeutic drugs has been assessed in two mouse tumors. Regrowth delay has been used as the assay, and by producing dose-response curves the effect has been classified as additive or interactive. A very small additive effect was seen with bleomycin and adriamycin. A larger additive effect was seen with cyclophosphamide, and a dose dependent interaction was seen with melphalan. The misonidazole dose needed to produce these effects has a threshold of 0.5--0.75 mg/g. Two other nitroimidazoles (Ro 05-9963 and Ro 03-8799) were no more effective than MISO when used with melphalan or cyclophosphamide, even though Ro 05-9963 was much more cytotoxic as a single agent. A distinct enhancement of normal tissue toxicity (LD50/30) was observed for MISO combined with melphalan or cyclophosphamide in two strains of mice. However, the tumor sensitization was bigger than the normal tissue effect, resulting in a therapeutic gain in 3 out of 4 comparisons.