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

5-Halo-6-phenyl pyrimidinones, represented by 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and 2-amino-5-iodo-6-phenyl-4(3H)-pyrimidinone (AIPP), and 8-substituted guanosines, represented by 8-bromoguanosine (8-BrGuo) and 8-mercaptoguanosine (8-MGuo), are well-documented biological response modifiers. We have found that these substituted pyrimidinones and guanosines are very similar in their abilities to activate B cells. ABPP, AIPP, 8-BrGuo, and 8-MGuo induced murine B cells to polyclonally proliferate and differentiate in vitro. The maximal B-cell response levels and the kinetics of the responses elicited with both classes of compounds were comparable; however, ABPP and AIPP were approximately 10-fold more potent than 8-BrGuo and 8-MGuo. An additional similarity observed between the two classes was that polyclonal activation of B cells by ABPP, AIPP, 8-BrGuo, and 8-MGuo was limited to large B cells which had probably been activated previously in vivo. This is in contrast to lipopolysaccharide which is capable of inducing both large, activated B cells and small, resting B cells to proliferate and differentiate. Although substituted pyrimidinones and guanosines were not able to induce new DNA synthesis or antibody production in small B cells, both classes of compounds increased the expression of Ia antigens on the surface of both small and large B cells. These data, together with the recent observations that 8-BrGuo, like ABPP and AIPP, can stimulate NK and cytotoxic macrophage activity via the induction of interferon, strongly suggest that 5-halo-6-phenyl pyrimidinones and 8-substituted guanosines belong to the same structural class of biological response modifiers. Thus, the residues held in common by these two classes of stimulators may interact with the same cellular constituent in the target cells.

Topics: Animals; B-Lymphocytes; Cell Differentiation; Cytosine; Female; Guanosine; Histocompatibility Antigens Class II; Interphase; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Thionucleosides

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

We investigated the effect of therapeutically relevant pyrimidinone molecules on murine natural killer (NK) cell cytotoxicity. Our studies demonstrated that pyrimidinones augmented or induced substantial levels of NK cell anti-YAC-1-directed cytotoxic potential in the spleen, bone marrow, peripheral blood, peritoneal exudate, lungs, and liver of adult and infant mice. The NK cell stimulating effect of pyrimidinones was not restricted to a single mouse strain, but was displayed by six different inbred strains of mice. Percoll density gradient separation studies demonstrated that activated effector cells were of low density, displayed morphology of large granular lymphocytes (LGL), and expressed asialo GM-1 cell surface antigen. The analysis of the mechanism of NK cell potentiation showed that the increase in the cytotoxic activity was manifested on several levels, including an increased kinetics of lysis and an increase in the number of LGL and in their tumor-binding and killing capacity. Furthermore, the pyrimidinone-mediated NK cell-augmenting effect was abolished by anti-interferon serum, indicating the role of interferon in NK cell potentiation. In the light of possible role of NK cells in cancer defense, pyrimidinones may have therapeutic value in defense against primary and metastatic tumors.

Topics: Adjuvants, Immunologic; Aging; Animals; Cell Separation; Cytosine; Cytotoxicity, Immunologic; Female; Interferons; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred Strains

Topics: Animals; Antineoplastic Agents; Cytosine; Interferon Inducers; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Phagocytosis

The modulation of murine host resistance to infection with Listeria monocytogenes by the substituted pyrimidine anti-viral compounds, 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP), 2-amino-5-bromo-6-phenyl-4-pyrimidinol (ABPP) and 2-amino-5-iodo-6-phenyl-4-pyrimidinol (AIPP) was investigated. BAF1 mice given three daily injections of ABMP, ABPP (as well as of the interferon-inducer poly I:C) demonstrated enhanced anti-listerial resistance, as measured by a 100-fold increase in the median lethal dose of Listeria compared to vehicle-treated control mice. This enhancement was also detectable as a decrease (up to 100-fold) in the number of viable Listeria recoverable from the livers and spleens of mice during the non-immune phase of natural resistance (24-72 h following infection) to this pathogen. In contrast, AIPP did not enhance anti-listerial resistance. Since each of the effective agents have been shown to induce the production of interferon, the role of interferon in the mechanism of natural resistance to Listeria was evaluated. The serum of untreated B10.A mice infected with Listeria was shown to contain high levels of interferon. Treatment of these mice with a potent anti-mouse interferon antibody preparation completely neutralized circulating interferon activity; however, such treatment had no apparent effect on the growth of Listeria. In addition, mice which received injections of both ABMP and anti-interferon demonstrated a level of resistance identical to that seen in mice given ABMP and normal serum. Based on these results, we propose that although interferon is produced in response to listerial infection, interferon is not a critically important mediator in the mechanism of natural resistance to this pathogen. Furthermore, it appears that the immunomodulating activity of these experimental compounds does not involve interferon.

Topics: Animals; Cytosine; Female; Immunity, Innate; Interferon Inducers; Listeriosis; Male; Mice; Pyrimidines

Several 5-halopyrimidinones have been shown to have many different biological activities. These include interferon induction, antitumor effects, modulation of immune responses, and polyclonal B-cell activation. The present study was carried out to determine the effects of treatment of mice with two 5-halopyrimidinones, 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and 2-amino-5-iodo-6-phenyl-4(3H)-pyrimidinone (AIPP), on the murine cytochrome P-450 system. Administration of ABPP or AIPP to mice by a dosage regimen similar to that resulting in interferon induction by these chemicals resulted in a significant depression in liver cytochrome P-450 levels. These results suggest that 5-halopyrimidinones can depress cytochrome P-450 levels and that this depression may affect the metabolism of other drugs by cytochrome P-450.

Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Cytosine; Female; Mice; Microsomes, Liver

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