This is the continuation of a research program on purine antimetabolites. the investigations proposed are in four areas, all involving the actions of adenosine analogs. 1. Further studies on adenosine deaminase: improved methods of purification of the human enzyme will be developed; further studies of tight-binding inhibitors, coformycin and deoxycoformycin (dCF) will be performed including comparisons of their interactions with the nucleoside transport system (NTS); temperature dependence of the ADA reaction and its inhibition by deoxycoformycin will be studied. The dCF-ADA inhibition method will be used to study temperature dependence of the NTS and its interaction with transport inhibitors, e.g. NBMPR, dipyridamole. Other topics are the behavior of immobilized ADA, chirally-specific isomers of EHNA, and the synergy between dCF and various adenosine analogs. 2. Further studies of methylthioadenosine phosphorylase (MTA-Pase) Substrate analogs have been identified that release cytotoxic adenine analogs, 5 -substituted ribose-1 phosphates or both. Potent inhibitors of MTA-Pase, e.g. 5'-iodoformycin, will be examined further with the above substrates for antitumor actions. Activities of the enzyme in normal and malignant tissues will be studied and modulations during cell cycle, etc. Combinations of cytotoxic substrates and other agents will be studied, e.g. cell cycle specific drugs, inhibitors of polyamine synthesis. 3. Effects of adenosine analogs on blood platelet aggregation. Inhibitors of aggregation such as 8-selenoisouronium C-IMP, methylthioadenosine analogs and various adenosine analogs will be studied. 4. A micro-level system is used to identify chemotherapeutic adenosine analogs received from medicinal chemistry colleagues. These methods enable accurate evaluations on quantities of 25 milligrams or less.
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