Methionine S-adenosyltransferase (MAT) is a cytoplasmic enzyme that condenses methionine (Met) with ATP to form S- adenosylmethionine (AdoMet). It is present in almost all rat and human normal tissues exclusively in one isozymic form, M-2, whereas in highly malignant rat and human tumor tissues it is mainly or exclusively in another form, M-T, unique to tumor tissues. M-T is thus an attractive target in cancer chemotherapy, particularly since MAT is the sole source of AdoMet, the obligatory methyl donor in more than 35 transmethylation reactions. It is proposed to design compounds that can diffuse into cells and become converted to potent inhibitors selective for human M-T with respect to human M-2. Certain ATP-Met covalent adducts are potent but nonselective inhibitors of M-T and M-2. Further, a brief survey has shown that ATP derivatives bearing a single short substituent at any of several atoms could selectively inhibit M-T and bind to M-T as well as does ATP itself. It is proposed to introduce one or two such substituents into an ATP-Met adduct for the purpose of imparting M-T selectivity whilst retaining inhibitory potency. Studies with other isozymes provide a precedent for success with this approach. One or both substituents will then be systematically elaborated in order to increase the level of selectivity (enhancements of greater than 103 have previously been reported with this procedure). The M-T inhibitors so derived will be converted to non-anionic derivatives that hopefully are membrane-permeable and can regenerate the parent inhibitor intracellularly. Promising structures for this purpose are tetra(acyloxymethyl) phosphoesters because recent evidence indicates that bis(acyloxymethyl) esters of 5'- mononucleotides are membrane-permeable and regenerate the free nucleotides inside cells. If any cell-permeating M-T inhibitors inhibit MAT more powerfully in human tumor cells than in mouse normal cells in vitro, they will be tested for in vivo antineoplastic activity against human colon, lung, cervical, or stomach carcinomas growing in athymic mice. M-T is sometimes the sole species of MAT in these human carcinomas growing in mice, and it is possible, therefore, that the studies could lead to much-needed drugs effective against these high-morbidity malignancies.
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