Many solid
tumors and
hematologic malignancies lack expression of the
enzyme methylthioadenosine phosphorylase (MTAP), due either to deletion of the MTAP gene or to methylation of the MTAP promoter. In cells that have MTAP, its natural substrate, methylthioadenosine (
MTA), generated during
polyamine biosynthesis, is cleaved to
adenine and 5-methylthioribose-1-phosphate. The latter compound is further metabolized to
methionine.
Adenine and
methionine are further metabolized and hence salvaged. In MTAP-deficient cells, however,
MTA is not cleaved and the salvage pathway for
adenine and
methionine is absent. As a result, MTAP-deficient cells are more sensitive than MTAP-positive cells to inhibitors of de novo
purine synthesis and to
methionine deprivation. The challenge has been to take advantage of MTAP deficiency, and the changes in metabolism that follow, to design a strategy for targeted treatment. In this review, the frequency of MTAP-deficiency is presented and past and recent strategies to target such deficient cells are discussed, including one in which
MTA is administered, followed by very high doses of a toxic
purine or
pyrimidine analog. In normal host cells,
adenine, generated from
MTA, blocks conversion of the analog to its toxic
nucleotide. In MTAP-deficient
tumor cells, conversion proceeds and the
tumor cells are selectively killed. Successful mouse studies using this novel strategy were recently reported.