Development of companion diagnostics and molecular target therapy in malignancy : a model of the purine metabolic enzyme deficiency

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Methylthioadenosine phosphorylase (MTAP) is an enzyme involved in the metabolism of purine and methionine. Genetic analysis of the MTAP-negative cancer cell lines indicated that the all enzyme-negative cell lines but one had the partial or total deletion of MTAP gene. When this exceptional cell line was incubated with 5'-deazacytidine, the MTAP gene expression was confirmed by RT-PCR, indicating that the promoter hypermethylation is one of the mechanisms for MTAP deficiency in malignancy. In addition to IHC and Western blotting with anti-human MTAP monoclonal antibody, FACS analysis was found to be useful for the diagnosis of MTAP deficiency in leukemic cell lines.In conclusions, MTAP deficiency will be diagnosed more precisely with IHC and FACS analysis than with the genetic test alone. Since the frequency of MTAP deficiency in a variety of primary tumors is relatively high, one could exploit this metabolic difference between normal and cancer cells for the development of the selective chemotherapy. Furthermore, the combination of MTAP deficiency as a molecular target and the selective chemotherapy is a good example of companion diagnostics.