Delayed cytotoxicity of 6-mercaptopurine is compatible with mitotic death caused by DNA damage due to incorporation of 6-thioguanine into DNA as 6-thioguanine nucleotide

Many protocol studies have shown that low dose B-mercaptopurine (6MP) in ma intenance chemotherapy for childhood acute lymphoblastic leukemia (ALL) can be utilized to cure the disease. Mitotic or reproductive cell death has be en recognized after G2 arrest when cells are treated with antitumor agents. The precise mechanism of mode of action of 6MP still remains unclear. We f ound delayed cytotoxic effect of 6MP in P388 murine leukemic cells. Morphol ogical study showed that 6MP induced delayed death was characterized by an enlargment of cell size and multinucleated nuclei. Agarose gel electrophore sis of fragmented DNA from cells treated with 6MP showed the typical ladder pattern. These findings were compatible with mitotic death. Our results make us hypothensize that the delayed cytotoxicity of 6MP is on e of the drug induced mitotic deaths caused by DNA damage due to incorporat ion of 6-thioguanine (6TG) into DNA as thioguanine nucleotide (TGN), Mitoti c death may be a mechanism for killing the cycling cells from residual leuk emic cells in GO or long G1 phases in the treatment of childhood ALL.