The long range goal of this program is to improve the therapy of human cancer with arabinonucleoside analogs. This project is concerned with the mechanism responsible for the selectivity of established and new arabinonucleosides related to cytosine, adenine and guanine in murine leukemia and human lumphoid model systems. The following specific aims will be sought: Further aspects of the cytotoxic mechanism of newly synthesized purine and pyrimidine deaminase-resistant 2'-0-nitronucleosides termed nitrara-A and nitrara-C of arabinosyl-adenine and -cytosine, respectively in human lymphoblastoid lines; use radiolabeled nitrara-C and high pressure liquid chromatography to determine its metabolic fate in plasma and activation (phosphorylation and incorporation into nucleic acids) in murine leukemia and in human lymphoblastoid lines, including those of T and B origin, with demonstrated differential sensitivity to the drug; Evaluate in collaborative studies with colleagues from this institution and elsewhere the antitumor and antiviral effects of the new nitrate nucleosides and purine nucleoside phosphorylase-resistant 9-Beta-D-arabinosylguanine in animal model systems; purify and characterize the nucleotidase enzymes in human lymphoid tissues for degradation of active arabinonucleotides and deoxynucleotides; specific antibodies to nucleotidases will be obtained to aid in the identification of the enzyme(s) responsible in human lymphoblastoid of T and B origin (wild type and mutants) for the catabolism of the arabinonucleotide analogs. Nucleotidase activity and analog nucleotide retention will be examined in sensitive and resistant cell lines to further define the relationship of these two to arabinonucleoside metabolism and selectivity.
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