pyrimidinones and 2-amino-5-iodo-6-phenyl-4-pyrimidinone

Therapeutically active pyrimidinones such as 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP, Bropirimine) are known to be potent immuno-modulators. This includes their ability to markedly augment murine natural killer (NK) cell activity as measured in ex vivo NK assays. We now report the use of a murine in vivo NK assay, based on the rate of NK-cell mediated clearance of radiolabeled tumor cells from the lungs, to directly demonstrate in vivo NK augmentation by several pyrimidinones, including ABPP. In order to evaluate the involvement of the cytokines interferon (IFN), interleukin-1 (IL-1), and interleukin-2 (IL-2) in ABPP-induced NK augmentation, we first showed that injection of purified IFN or IL-1, but not IL-2, resulted in significant enhancement of in vivo NK activity. However, the mixture of IFN, IL-1, and IL-2 synergistically enhanced NK activity more than with any of the cytokines alone. We then showed that ABPP induced significant serum levels of IFN and IL-1, but not IL-2. The induction of IL-1 by ABPP in vivo was further verified by demonstration of increased serum levels of the acute phase protein serum amyloid P in ABPP-treated mice. The possible induction of IL-2 by ABPP was further investigated by using cyclosporin A (CsA) to inhibit IL-2 production in vivo. No diminution of ABPP-induced NK augmentation was seen, however, in CsA treated mice. These results suggest a role for IFN and IL-1 in the augmentation of NK activity in vivo by ABPP, but no evidence for a role for IL-2 was found.

Topics: Animals; Biological Products; Cytokines; Cytosine; Drug Synergism; Female; Interferons; Interleukin-1; Interleukin-2; Killer Cells, Natural; Mice; Mice, Inbred Strains; Poly I-C; Pyrimidinones

Since pyrimidinone compounds induce interferon production in several animal species and have potent antivirus activities, it appeared important to determine whether these compounds could also induce antitumor activities in their recipients. Pyrimidinone compounds 2-amino-5-bromo-6-methyl-4-pyrimidinone (ABMP), 2-amino-5-brome-6-phenyl-4-pyrimidinone (ABPP), and 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) were studied for their activities against artificial lung metastases of the weakly immunogenic spontaneous fibrosarcoma NFSa, the moderately immunogenic spontaneous mammary carcinoma MCa-K, and the strongly immunogenic 3-methylcholanthrene-induced fibrosarcoma FSa syngeneic to inbred C3Hf/Kam mice. In addition, the therapeutic efficacy of ABPP and AIPP was also determined against spontaneous lung metastases of NFSa. ABPP and AIPP given ip at 250 mg/kg for 2 or 3 consecutive days before or after iv inoculatin of NFSa, FSa, or MCa-K cells greatly reduced the number of tumor nodules developed in the lungs. ABMP, however, was considerably less effective. ABPP and AIPP were also effective in therapy of spontaneous lung metastases of NFSa, especially when these compounds were given before surgical removal of the primary tumor. Neither ABPP nor AIPP was effective against tumor nodules growing in whole-body irradiated (WBI) mice, but both protected mice against enhancement of lung metastasis formation induced by exposure to whole-body irradiation. ABPP was more effective than AIPP in inducing production of interferon in normal mice. When treated with ABPP, WBI mice, however, were unable to produce interferon. These results show that 6-phenyl-pyrimidinone compounds induce strong antitumor activities in mice, which correlated with neither tumor immunogenicity nor the ability of these agents to induce interferon, but which depended on the immune status of the tumor host.

Topics: Animals; Cytosine; Dose-Response Relationship, Drug; Fibrosarcoma; Immunity, Innate; Interferon Inducers; Interferons; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Pyrimidinones; Time Factors; Whole-Body Irradiation

Topics: Animals; Cytosine; Female; Immunity; Interferon Inducers; Interferons; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Virus Diseases

The interferon inducing characteristics of a new series of 6-phenyl pyrimidinol compounds are described and compared against a previously identified pyrimidine, 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP). Interestingly, a split in ability to induce interferon but not in vivo antiviral activity was observed in the newest compounds. One representative compound, 2-amino-5-bromo-6-phenyl-4-pyrimidinol (ABPP) induced high levels of serum interferon in mice, cats and cattle in vivo and human lymphoid tissue in vitro and was consistently more active than ABMP. Another representative compound, 2-amino-5-iodo-6-phenyl-4-pyrimidinol (AIPP) was a poor interferon inducer in every system evaluated yet was as active as an in vivo antiviral agent as ABPP or ABMP. The serum interferon response induced by both ABMP and ABPP appeared to originate from an antilymphocyte serum resistant but radiosensitive cell population in the thymus and spleen. These results suggest that the antiviral activity of this group of agents is mediated by both interferon and interferon independent mechanisms.

Topics: Animals; Antiviral Agents; Cats; Cattle; Cells, Cultured; Cytosine; Encephalomyocarditis virus; Female; Fibroblasts; Humans; Hydrocarbons, Halogenated; Interferon Inducers; L Cells; Mice; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Semliki forest virus; Vesicular stomatitis Indiana virus