Thiopurine induced disturbance of DNA methylation in human malignant cells.

The studies described indicate that me-t-IMP formation is an important pathway, contributing to cytotoxicity in Molt F4 cells, which exhibit a highly active de novo purine synthesis. On three levels cytotoxicity is induced during methylation of thiopurines. 1. Purine synthesis de novo is inhibited during formation of me-t-IMP. Inhibition of PDNS results in depletion of purine nucleotides, with subsequently diminishing DNA and RNA synthesis. 2. The increased PRPP levels, induced by me-T-IMP, induce increased pyrimidine biosynthesis and cause an imbalance in purine nucleotides. This imbalance may lead to inhibition of cell growth and after prolonged exposure, to cell death. 3. The observed depletion of SAM and the decrease of the SAM/SAH ratio may be an additional mechanism by which 6MP and me-MPR exert their effects on cell growth and cell viability. Changes in SAM/SAH ratio may directly influence methylation reactions. The significant decrease of DNA methylation by 6MP and me-t-IMP may influence gene regulation and tumor progression. Administration of SAM leads to chemoprevention of rat liver carcinogenesis, indicating a role of DNA methylation in tumor progression. Besides the effects on methylation of DNA, a decrease of SAM/SAH ratio may also affect other processes, such as methylation of RNA, proteins and phospholipids, thereby disturbing their functionality. In conclusion, decrease of the SAM/SAH ratio resulting from treatment with 6MP and me-MPR may exert many effects in these cells. This may open a new field of research, possibly contributing to a deeper understanding of the complex mechanisms by which 6MP provokes cytotoxicity.