The overall purpose of this project is to understand differences in MTA metabolism between normal cells and MTAase-deficient (MTAase-) malignant cells and to develop a rationale for the treatment of MTAase- tumors with a regimen consisting of methionine restriction and methotrexate. The applicant recently completed an analysis of 100 cases of acute leukemia and found that 10 were MTAase-. The frequency of the enzyme deficiency was particularly high (38%) in T-cell acute lymphoblastic leukemia (ALL). He intends to extend these studies by determining if MTAase deficiency occurs frequently in other forms of T-cell malignancy such as T-chronic lymphocytic leukemia and T-cell lymphoma. In addition, he will use MTAase+ and MTAase- cell lines to explore the use of methotrexate, a drug which interferes with both methionine recycling and adenine nucleotide synthesis, for the selective killing of MTAase- malignant cells in vitro and in vivo. He will also determine if the effect of MTX on MTAase-cells is enhanced by concomitant methionine restriction. Finally, the applicant intends to purify human MTAase to homogeneity (a 1000-fold enrichment has already been achieved) and to use amino acid sequence analysis of this material (plus an alternative approach in yeast) in an effort to clone the MTAase gene. Molecular probes generated during this effort will be utilized to determine the chromosomal location of the structural gene for MTAase and to characterize the defect causing MTAase deficiency in malignant cells.
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