Analysis of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced DNA damage in tumor cell strains from Japanese patients and demonstration of MNNG hypersensitivity of Mer−xenografts in athymic nude mice

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Abstract
Among 15 human tumor cell strains from Japanese patients, 1 strain derived from a patient with thyroid cancer showed inability to support the growth of adenovirus 5 treated with N-methyl-N''-nitro-N-nitrosoguanidine (MNNG). When plated on this Mer- strain, adenovirus 5 showed 3-4 times higher sensitivity to MNNG-induced killing than when plated on any of the other 14 Mer+ tumor cell strains. Biochemical analysis showed that the Mer- strain was defective in demethylation repair of O6-methylguanine produced by MNNG treatment. The sensitivities of 12 of the 15 human tumor strains, including the Mer- strain, to MNNG were compared by measuring their colony-forming abilities. All the strains tested showed the Rem- phenotype (having higher sensitivity to MNNG-produced cell killing than normal fibroblasts). The differential killing effects of MNNG on Mer- and Mer+ tumor cells under in vivo conditions were tested using the Mer+ HeLa S3 strain and its Mer- variant. Mer+ cells and Mer- cells were implanted subcutaneously into the left and right flanks, respectively, of 10 nude mice and the next day, MNNG solution (0.25 ml at 1 mg/ml) was injected into the implantation sites of 8 mice. Mer- tumor cells in 6 of 8 treated mice showed no growth and those in the other 2 mice did grow, but regressed after .apprx. 3 wk. In contrast, Mer+ tumor cells continued to grow in all the 8 mice treated, indicating that Mer- tumor cells may be selectively inactivated by suitable therapeutic regimens with appropriate methylating drugs.