The suppression of metallothionein synthesis inhibits the growth of leukemia P388 cells

Metallothionein (MT) isoforms, by regulating the homeostasis of zinc, influence aspects of molecular and cellular biology and regulate events over a wide rage of physiological and/or pathological parameters. For example, tumor cells with acquired resistance to antineoplastic agents over-express MTs. By using MT-I antisense phosphorothioate oligodeoxyribonucleotide (ODN) (18-mer) complementary to the intron 2/exon 3 splice site of the mouse MT-I and human MT-If mRNA, we learned that MT-I antisense ODN caused a suppression of MT synthesis and hence inhibited the growth of Leukemia P388 cells, Ehrlich carcinoma cells and sarcoma 180 cells in a dose-and time-dependent fashion; whereas, MT-II antisense ODN inhibited the growth of Chinese hamster lung V79 cells. Moreover, treatment with MT-I antisense ODN attenuated the growth and progression of tumors in mice. The tumor inhibitory effects of MT-I antisense ODN, evident in both in vivo and in vitro systems, was specific since ceruloplasmin antisense ODN was devoid of any action. The results of these studies are interpreted to suggest that the growth of neoplastic cells depends on the expression of MT, and in this area, MT-I and the MT-II exhibit distinct actions, which may provide a unique avenue for chemotherapy against certain neoplasms.