5-halo-6-phenyl pyrimidinones: new molecules with cancer therapeutic potential and interferon-inducing capacity are strong inducers of murine natural killer cells.
We tested the effect of three different interferon-(IFN) inducing pyrimidinone molecules with cancer therapeutic potential on natural killer (NK) cells. Peritoneal exudate (PE) cells were selected for these studies because their NK cell cytotoxicity is very low. Augmentation of PE-NK cell cytotoxicity was observed in eight different strains of mice after i.p. administration of 250 mg/kg of each of the pyrimidinones. NK cell induction occurred as early as 6 hr after pyrimidinone administration and peaked 2 to 4 days after treatment; at that time, cytotoxicity was as high as 60 to 90%. Augmentation of NK cell activity was independent of IFN serum levels induced by pyrimidinones and murine H-2 haplotype, and did not exhibit any histocompatibility or species-specific restriction, because it was expressed to syngeneic, allogeneic, and xenogeneic tumor target cells. Characterization studies demonstrated that the cytolytic cells were not macrophages, T cells, or B cells and exhibited NK cell characteristics. NK cell tumor-binding and tumor-killing studies demonstrated that NK cell augmentation was accomplished via both activation and recruitment of NK cells. If one considers NK cells as an important part of tumor immunity (as indicated by murine studies), pyrimidinone molecules may be effective anticancer agents.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001202:Ascitic Fluid / Q000166:cytology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D007369:Interferon Inducers / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D007369:Interferon Inducers; D011744:Pyrimidinones