The proposal is a continuing study of the mechanism and selectivity of action of pyrimidine nucleoside derivatives that have chemotherapeutic activity. Two specific projects are of current interest: 1. Metabolism and Effects of 2'-Fluoro-5-Iodo-1-beta-D-Arabinofuranosyl Cytosine (FIAC) in Human, Murine Leukemic Cells and Virus-Infected Cells. A new potent antiherpesvirus compound, FIAC (ED50 is less than 0.01 micromoles), inhibits the growth of human tumor cell lines in culture (ED50 is less than 0.1 micromoles) but is less inhibitory to P815 murine leukemic cells. It is proposed that FIAC be studied in human leukemic, murine leukemic cells to explore the biochemical basis for the selectivity of its cytotoxic and antiviral effects. Bone marrow and/or peripheral leukemic cells from patients with different types of leukemia, P815 cells and herpes simplex virus I-infected and non-infected Vero cells will be used. To be studied are 1) the effect of FIAC on metabolism of tritiated natural nucleosides; 2) the metabolism of (2-14C)FIAC in different cells, i.e., deamination, phosphorylation and incorporation into DNA and/or RNA and the identity of the labeled moiety(ies) in nucleotides and nucleic acids; 3) the effects of natural nucleosides on the metabolism of (2-14C)FIAC. 2. Transport and Metabolism of (2-14C)Pseudoisocytidine (14C-psi IC). Psi IC is a new C-nucleoside that is effective against p815 cells and its subline resistant to ara-C. Preclinical studies in this laboratory showed an accumulation of 14C-psi IC by rat liver and Phase I clinical trials manifested hepatotoxicity. In this project, isolated hepatic cells of rats and P815 cells sensitive and resistant to psi IC will be used to study the transport of (14C)psi IC by a double syringe rapid mixing apparatus and an oil-layer rapid separating technique.
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