Misonidazole-induced chemopotentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea toxicity in O6-methylguanine-DNA methyltransferase proficient (Mer+) and deficient (Mer-) cell lines.

The radiation sensitizing agent misonidazole (MISO) was combined with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of Mer+ (IMR-90, HeLa, and HeLa-S3) and Mer- (EMT-6/Ro, VA-13, and HeLa-MR) cell lines under hypoxic conditions in vitro. The magnitude of enhancement achieved by the addition of MISO was calculated by comparison with survival curves obtained by treating each cell line with CCNU alone, under hypoxic conditions. As expected, the Mer+ cells were more resistant to CCNU treatment than were their Mer- counterparts. In the presence of 1.0 mM MISO the toxicity of CCNU was enhanced (dose enhancement factor, 1.4-1.6) in all three of the Mer- lines. However, the Mer+ lines were less responsive to chemopotentiation by MISO. The toxicity of CCNU toward two of the Mer+ lines, IMR-90 and HeLa, was not modified by the addition of MISO, while a slight enhancement (dose enhancement factor, 1.2) was observed in the HeLa-S3 line. Similar results were obtained with IMR-90 and VA-13 cells treated by postincubation in which aerobic CCNU treatment was followed by hypoxic exposure to MISO for up to 6 h. While no correlation was observed between Mer status and the hypoxic toxicity of MISO, the data suggest that a relationship might exist between chemopotentiation and MISO sensitivity when each phenotype is considered separately. These observations suggesting that tumor cells of the Mer+ phenotype may be less responsive to MISO chemopotentiation have significant implications for ongoing and planned clinical trials designed to evaluate the potential of chemopotentiation using CCNU and MISO since greater than 75% of human tumors are Mer+.