INDUCTION OF APOPTOSIS IN NEOPLASTIC-CELLS BY DEPLETION OF VITAMIN-B-12

Methionine synthase, a critical enzyme in deoxyribonucleotide biosynth esis for DNA replication, requires vitamin B-12 as a cofactor. We have tested the hypothesis that depletion of cells of vitamin B-12 would b lock growth of neoplastic cells and divert them into apoptosis and cou ld form the basis of a new therapeutic strategy for cancer treatment. Using nitrous oxide to inactivate vitamin B-12 we show that, in a vari ety of cell lines in vitro, methionine synthase is rapidly inhibited, the cells cease proliferation and undergo apoptosis. The kinetics of c ell death, once started, are similar to those observed following metho trexate treatment or serum withdrawal. This is the first observation o f apoptosis being induced following depletion of an essential metaboli te as opposed to the more conventional strategy of adding a toxic drug to damage cells thereby triggering apoptosis. Moreover, vitamin B-12 depletion has no effect on the nonproliferating cell population.