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PubMed1979

Activation of mouse macrophages by pyran copolymer and role in augmentation of natural killer activity.

Inoculation of mice with pyran copolymer resulted in activation of natural killer (NK) cells as well as macrophages. Conditions optimal for the boosting of NK activity seemed to differ from those optimal for macrophage activation as assessed by cytostasis of tumor target cells. Peak levels of macrophage cytostatic reactivity were found at about 7 days after drug injection and were only achieved by the highest doses of pyran tested. Macrophage activation was consistently higher in the peritoneal cavity than in the spleen, regardless of route of administration, in contrast to the failure of i.v. pyran to induce high NK reactivity in peritoneal exudate cells. At 2-3 days after pyran treatment of older mice, NK augmentation reached peak levels, but only minimal macrophage activation was found. Despite these differences, macrophages played a role in regulating NK activity in pyran-treated mice. Functional macrophages appeared to be required for augmentation of NK activity by pyran, since boosting was impaired by prior in vivo inoculation of silica. Macrophages also appeared able to inhibit NK activity. In younger mice that exhibited high spontaneous levels of NK activity, pyran treatment produced a substantial reduction in NK activity to levels below those of untreated mice. This depression coincided with the time of peak levels of macrophage cytostasis. Furthermore, removal of adherent cells from the spleen cells of these pyran-treated mice resulted in levels of NK activity almost as high as those of untreated mice. The possibility that the depression of NK activity in young mice by pyran copolymer is due to suppressor cells is discussed.

Animals↗
PubMed1984

Cryptococcus neoformans: in vivo protection of mice by pretreatment with pyran copolymer.

Synthetic polyanions have been shown to alter host resistance to infection. The anticryptococcal effect of pyran copolymer was assessed in vivo and in vitro. Pretreatment with pyran copolymer significantly extended mean survival in mice lethally infected with Cryptococcus neoformans when compared to untreated animals (p less than 0.01). The anticryptococcal effect of peritoneal exudate cells (PEC) elicited by 10% thioglycollate or pyran copolymer (25 mg/kg) was assessed in vitro. Initial percent phagocytosis of both encapsulated and non-encapsulated isolates of C. neoformans was greatest in the pyran elicited PEC. Significant killing of C. neoformans in vitro was observed only in pyran-activated PEC cultures combined with non-encapsulated cells of C. neoformans, although pyran PEC did inhibit initial growth of phagocytized encapsulated yeast cells. The protection of pyran copolymer pretreated mice from infection with C. neoformans, but the absence of significant killing of encapsulated yeast in vitro suggest a complex mechanism of host defense which may involve an activation of the reticuloendothelial system by pyran copolymer.

Animals↗
PubMed1983

Effect of pyran copolymer on activation of murine macrophages: evidence for incomplete activation by use of functional markers.

The degree of activation of peritoneal macrophages elicited by pyran copolymer (MVE-2) was studied in C57BL/6J mice. When cytotoxicity was examined under endotoxin-free culture conditions, the pyran-elicited macrophages could not complete cytolysis of tumor target cells. The macrophages, however, completed cytolysis when pulsed with endotoxin. These results were obtained when either the interval between injection of the pyran copolymer and harvest of the macrophage or the dose of pyran was varied. The pyran-elicited macrophages expressed five markers considered to be typical of inflammatory macrophages, and bound tumor cells to an augmented degree. The pyran-elicited macrophages were capable of secreting a potent cytolytic proteinase when pulsed with endotoxin, but did not secrete cytolytic proteinase spontaneously. The pyran-elicited macrophages, in contrast to inflammatory macrophages, could effect cytostasis of tumor cells; their cytostatic potential was also augmented by addition of endotoxin. Taken together, the results indicated that pyran copolymer elicits primed but not fully activated murine macrophages.

Animals↗
PubMed1981

Inhibition of the classical and alternative pathways of human and guinea pig complement by pyran copolymer.

The ability of pyran copolymer to interact with the classical and alternative pathways of complement was assessed in human and C4-deficient guinea pig serum. Pyran induced a dose-dependent inhibition of hemolytic activity in both serum systems. Immuno-electrophoretic analysis of pyran-treated human serum revealed that C3 was not cleaved. Factor B was altered into a more anionic mobility which was not similar to biologically cleaved Ba or Bb fragments. Pyran-treated serum was unable to lyse antibody-coated erythrocytes (EA or EA coated with C1 and C4 and EA coated with C1, C4 and C2. Pretreatment of serum with ethylenediaminetetraacetic acid did not prevent inhibition of hemolytic activity by pyran. Cobra venom factor did not cleave C3 in the presence of pyran. These data indicate that pyran does not activate complement by standard mechanisms but does inhibit one or more of its components.

Animals↗
PubMed1976

[Chemical and pharmacological research on pyran derivatives. VI. 2-Dialkylamino-4-oxo-4H-naphto/1,2-b/pyrans and derivatives].

The 2-dialkylamino-4-oxo-4H-naphtho [1,2-b]pyrans are obtained by the reaction of N,N-dialkylethoxycarbonylacetamides with alpha-naphthol and with substituted alpha-naphthols. The products on treatment with formaldehyde and morpholine or piperidine or N-methylpiperazine are transformed into the 2-dialkylamino-3-dialkylaminomethyl-4-oxo-4H-naphtho [1,2-b]pyrans. Pharmacological investigation has shown that 2-dimethylamino (K 12164), 2-(N-ethyl, N-methyl)amino- (K 12087) and 2-diethylamino-4-oxox-4H-naphtho [1,2-b]pyran (K 12165) show clear neurotropic activity of the neuroleptic type whereas compounds of the isomeric series, 1H-naphtho-[2,1-b]pyrans, studied previously (1), show anticonvulsive and sedative activity. This difference in pharmacological activity has prompted a more complete comparative examination of the activity of the two series of compounds. Study of antagonism to the effects of reserpine by both 4H-naphtho [1,2-b]pyrans and 1H-naphtho [2,1-b]pyrans has shown that in the latter series the 1-oxo-3-dimethylamino- (K 8291), the 1-oxo-3-(N-ethyl, N-methyl)amino- (K 8409) and the 1-oxo-3-diethylamino-1H-naphtho [2,1-b]-pyran (K 8292) have marked neurotropic activity of the antidepressive type.

Antidepressive Agents↗
PubMed1975

Histopathology of the host response to Lewis lung carcinoma: modulation by pyran.

The growth and metastasis of sc transplanted Lewis lung carcinoma were inhibited in C57BL/6J mice by treatment with pyran copolymer. The mean volume of the tumors of pyran-treated animals was 15% that of the saline-treated controls at day 33 post transplantation. Thereafter, the carcinomas gradually increased in volume. Pulmonary metastasis was first observed histologically at day 28 after pyran treatment, compared to day 15 after saline administration. All saline-treated animals died by day 48, whereas 70% of those given pyran remained alive. Tumor necrosis was much more extensive in the lesions of pyran-treated mice. Although neutrophils and monocytes, but few lymphocytes, infiltrated the subcutaneous connective tissue above the neoplasms of animals receiving saline, few leukocytes were present in other connective tissue sites around the tumor. In contrast, treatment with pyran was characterized by a shift at an early interval from a predominance of neutrophils to a predominance of histiocytes and some lymphocytes in the connective tissue above and around the subcutaneous tumor. These cells were often closely associated with degenerate-appearing tumor cells. Additionally, activated macrophages removed from the peritoneal cavity of pyran-treated, tumor-bearing mice exhibited nonspecific cytotoxicity for tumor cells in vitro.

Animals↗
PubMed1985

Non-cytotoxic activity of pyran copolymer-induced macrophages associated with potentiation of tumour vaccine in recipient mice.

Mice inoculated with both L1210 murine tumour vaccine and pyran copolymer were more resistant to L1210 than those inoculated with either of these agents alone. Rabbit anti-mouse thymocyte globulin and silica reduced the augmented resistance of these mice, suggesting the involvement of activated anti-tumour T cells and macrophages in the augmented resistance. We studied the activation of these two cells separately and examined the possible contribution of pyran copolymer-induced peritoneal cells to the augmented resistance to an inoculation of live tumour. Pyran copolymer-induced peritoneal cells endowed the tumour vaccine-primed mice, but not unprimed mice, with resistance to implanted L1210 and, among those peritoneal cell populations, macrophages but not T cells were responsible for this effect since the activity was associated with a cell population which was adherent to nylon wool columns, sensitive to silica and insensitive to anti-Thy 1.2 antibody plus complement. The pyran copolymer-induced peritoneal cells had very little antiproliferative activity when tested against L1210 in vitro and mice inoculated with these peritoneal cells did not survive a challenge of live L1210 cells much longer (less than 1 day) than L1210 inoculated control mice. Furthermore, the survival of L1210 vaccine-primed mice inoculated with one-tenth the amount of live L1210 (10(2)) was still much shorter than that of mice primed with L1210 vaccine plus pyran copolymer and challenged with ten times as many (10(3)) live L1210 cells. Therefore, direct tumoricidal activity was probably not a major factor in the in vivo immunological augmenting activity of the pyran copolymer-induced macrophages.

Animals↗
PubMed1987

I-Ad antigen expression of pyran copolymer-induced peritoneal cells in tumor vaccine-primed mice and its association with the host antitumor response.

Mice inoculated IP with L1210 murine leukemia vaccine and subsequently with pyran copolymer-induced macrophages (pyran-M phi) lived for a prolonged time after live L1210 inoculation IP. Pyran-M phi as tentatively identified by anti-AcM.1 monoclonal antibody expressed I-Ad antigen in tumor vaccine-primed recipient mice and contributed to maintaining I-Ad antigen positive (I-Ad+) macrophages at high cell density in the peritoneal cavity of recipient mice. The relevance of these I-Ad+ cells to the host antitumor response was examined by experiments in which I-Ad+ cell density in the peritoneal cavity and host antitumor response behaved in a parallel fashion. Human interferon-alpha A/D, an agent selectively inhibiting Ia antigen expression, and silica, a general antimacrophage agent, strongly suppressed I-Ad antigen expression of peritoneal macrophages of tumor vaccine-primed and pyran-M phi-inoculated mice and, consistently with this, the antitumor response was nullified in these mice. Tumor vaccine-primed mice inoculated with sodium caseinate or thioglycollate-induced peritoneal cells did not survive L1210 inoculation and, in these mice, I-Ad+ peritoneal macrophages were suppressed in number as compared with those of tumor vaccine-primed and pyran-M phi-inoculated mice. These results warrant further study on the contribution of I-Ad+ macrophages to pyran copolymer-induced augmentation of the antitumor response in tumor vaccine-primed mice.

Animals↗
PubMed1978

Inhibition of deoxyribonucleic acid polymerases from human cells and from simian sarcoma virus by pyran.

Pyrans are co-polymers of divinyl ether and maleic anhydride. Four pyrans of various molecular weights more potently inhibited terminal deoxyribonucleotidyltransferase (EC 2.7.7.31) from a human cell line of acute lymphoblastic leukemia origin (Molt-4) than they did DNA polymerases alpha, beta and gamma from these cells and DNA polymerase from simian sarcoma virus. For example, the concentrations of one pyran required for 50% inhibition of terminal deoxynucleotidyltransferase, DNA polymerases alpha, beta and gamma and viral DNA polymerase were 0.9, 110, 125, 35 and 47 microgram/ml respectively. Quantitatively similar results were obtained with the other pyrans. Inhibition of these enzymes by pyran was dependent on the concentrations of both the bivalent cation and template/primer or initiator in assay mixtures, but not on the concentrations of the substrate (deoxyribonucleoside 5'-triphosphate), enzyme, or bovine serum albumin. These results suggested that pyran inhibited these enzymes by complexing bivalent cations, which caused a decreased affinity of template/primer or initiator for each enzyme and a decrease in enzyme activity.

Cell Line↗
PubMed1978

Effects of combined radiotherapy and immunotherapy with the use of pyran copolymer on murine fibrosarcoma.

A weakly immunogenic, 3-methylcholanthrene-induced, subcutaneous fibrosarcoma syngeneic to inbred C3H/HeJ mice was used. Pyran copolymer was injected either directly into the tumor, ip, or iv as soon as tumors appeared or when tumors were 8 mm in diameter. One, three, or five doses of pyran copolymer at 10 or 20 mg/kg/dose were injected, with multiple doses being given every other day. Pyran copolymer injected intratumorally once, three times, or five times significantly retarded tumor growth and prolonged the survival times of the hosts. Of the other routes and doses, only pyran copolymer given three times iv significantly retarded tumor growth, but none of these significantly prolonged the survival times of the hosts. Pyran copolymer alone did not induce any complete regression of tumor. Local tumor irradiation with a single exposure to 2,000 rads of X-ray induced complete regressions in some mice, but a higher percentage of tumor cure was observed when tumor irradiation was followed by pyran copolymer treatment.

Animals↗
PubMed1976

Antiviral effect of pyran against systemic infection of mice with herpes simplex virus type 2.

The immunomodulator pyran markedly protected 5-week-old mice from lethal intravenous infection with herpes simplex virus type 2. The 50% lethal dose was increased almost 100-fold in pyran-treated mice as compared with controls. Although the protection was not as marked in older mice (10 and 16 weeks old), there was a significant increase in mean survival time. When the pathogenesis of herpesvirus disease was monitored in control and drug-treated mice, the effect of pyran was most evident in the spinal cord, where virus was recovered from 20 of 25 control mice and from only 6 of 25 pyran-treated mice. There was also a significant reduction in the titer of virus present, and virus appeared later in the spinal cord of pyran-treated mice than in control mice. The protective effect of pyran was observed only when the drug was administered 24 h before viral challenge, was seen after both intraperitoneal and intravenous injection, and was not due to direct inactivation of the virus.

Age Factors↗
PubMed1972

Pyran and polyribonucleotides: differences in biological activities.

Maleic anhydride-divinyl ether copolymer (pyran) and the polyribonucleotides are both large polyanions with potent antiviral activity. However, they are biologically quite different. Interferon levels of 100 units or more/ml were associated with antiviral activity of polyribonucleotides. Interferon induction by pyran compounds was not primarily involved in antiviral resistance because preparations that did not induce interferon possessed antiviral activity equal to that of interferoninducing preparations. Both polyriboinosinic-cytidylic acid [poly (rI.rC)] and pyran increased the immune response to sheep erythrocytes in the Jerne hemolytic plaque-forming cell (PFC) assay, but their modes of immunoadjuvant action differed. On peak day, poly (rI.rC)-treated mice demonstrated 5.1 x 10(4) PFC/spleen (557 PFC/10(6) nucleated cells) and pyran-treated mice exhibited 4.5 x 10(4) PFC/spleen (299 PFC/10(6) nucleated cells), as compared with 2.7 x 10(4) PFC/spleen (261 PFC/10(6) nucleated cells) in controls. The compounds also differed in phagocytic alteration; polyribonucleotides did not affect phagocytosis whereas pyran produced a biphasic response. Both polyanions exhibited toxic inhibition of liver microsomal enzyme metabolism of type I and type II drugs. However, whereas pyran sensitized mice 50-fold to the lethal effects of endotoxin, the polyribonucleotides did not significantly sensitize mice to endotoxin.

Adjuvants, Immunologic↗
PubMed1975

Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor.

Pyran (divinyl ether-maleic anhydride) copolymer (NSC 46015) is a polyanion with interferon-inducing and macrophage-stimulating properties, and therefore it has been studied as a possible antitumor agent. Extensive studies using pyran as an adjuvant to chemotherapy against the LSTRA murine leukemia and the Lewis lung carcinoma were performed. Pyran was effective over a dose range of 0.1 to 100 mg/kg/day. Single and multiple dose schedules were both capable of producing significant numbers of cures or increasing life-span, but pyran was ineffective if used without remission inducing chemotherapy. Various molecular weights of pyran copolymer were compared against NSC 46015 for adjuvant activity as well. In general, NSC 46015 tended to be the most efficacious, but all the pyran sizes that were tested possessed significant activity.

Adjuvants, Immunologic↗
PubMed1976

Immune response of BALB/c X DBA/2F1 mice to a tumor allograft during pyran copolymer-induced tumor enhancement.

The immune response of BALB/c x DBA/2 F1 mice to a transplantable Moloney leukemia virus-induced tumor allograft (MBL-2) was studied to determine the mechanism of pyran copolymer-induced tumor enhancement. The relative levels of humoral, lymphocyte, and macrophage response were followed chronologically by in vitro cytotoxic microassays using 51Cr-labeled target cells. Although pyran increased the titer of humoral cytotoxic antibody, levels of humoral factors capable of abrogating lymphocytoxicity were not enhanced. Furthermore, splenic lymphocyte-mediated cytotoxicity, although slightly diminished in pyran-treated mice, was not significantly affected. Macrophages harvested from allograft-bearing animals exhibited marked tumoricidal activity, which was augmented by pyran treatment. This macrophage-associated activity was specific for MBL-2 cells and not attributable to cytotoxins elaborated into the culture medium. Pyran slightly activated macrophages from nonsensitized mice to become cytotoxic for MBL-2 cells; activation was not T-cell dependent. However, strikingly fewer macrophages infiltrated the allograft in pyran-treated animals as judged by both histopathology and direct measurement. The defect in the migration or deposit of macrophages at the allograft site may have contributed to tumor enhancement.

Animals↗
PubMed1977

Macrophage involvement in the protective effect of pyran copolymer against the Madison lung carcinoma (M109).

Pyran copolymer (NSC 46015) therapy markedly enhanced host resistance to a murine lung carcinoma (M109) implanted s.c. Multiple dose schedules were not significantly better than single doses at increasing lifespan. Although tumor necrosis was much more extensive in the lesions of pyran-treated mice, pyran copolymer was not directly toxic to M109 cells in vitro. A comparative histopathological study revealed an intense histiocytic reaction in the connective tissue surrounding the primary tumor in mice receiving pyran as compared to 0.9% NaCl solution-treated controls. Macrophages were often associated with necrobiotic tumor cells. Morphologically activated macrophages were recovered from pyran-treated animals which potently inhibited DNA synthesis of M109 tumor cells in vitro. This response peaked 6 days after drug treatment and was to a large extent specific for neoplastic cells. Our results from both in vivo and in vitro studies support the concept that pyran enhances host resistance to neoplasia by mobilization and activation of the reticuloendothelial elements of the host's defense.

Animals↗
PubMed1999

Synthesis of 5-hydroxy-2-(beta-D-ribofuranosyl)pyran-4-one from a pyranulose glycoside.

The synthesis of 5-hydroxy-2-(beta-D-ribofuranosyl)pyran-4-one (9) is described. Treatment of pyranulose glycoside with bromine in carbon tetrachloride afforded brompyranulose glycoside in 90% yield. The reaction of (6S)- and (6R)-4-bromo-6-hydroxy-6-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-6H- pyran-3-one (2) in acidic media was examined with the following results: the reaction of 2 with trifluoroacetic acid (TFA) in dioxane afforded a mixture of 5-hydroxy-2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyran-4-one (3) and its furan derivative 5-hydroxy-2-{5-(benzoyloxy)methyl]furan-2-yl}pyran-4-one (4), but the use of hydrochloric acid formed the bromofurfural, 3-bromo-5-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-2-furancarboxyal dehyde only. Acetylation of a mixture (3 and 4) with acetic anhydride facilitated product separation to give the corresponding acetates 5-acetoxy-2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyran-4-one (5) and 5-acetoxy-2-{5-[(benzoyloxy)methyl]furan-2-yl}pyran-4-one (6). Treatment of 5 with hydrazine afforded 3-hydroxymethyl-6-(beta-D-ribofuranosyl)-1H-pyridazin-4-one in 43% yield. Debenzoylation of 5 with aq ammonia gave 9 in 50% yield.

Anti-Bacterial Agents↗
PubMed1987

Studies on immunological effects of pyran. 1. Enhancement of antibody production in mice.

Pyran, when administered intravenously, enhanced antibody production in mice. The optimal dose seemed to be about 10 mg/kg body weight. Antibody titers of normal mice inoculated with pyran are usually 2 to 8 times higher than those of mice inoculated with normal saline. However, pyran does not affect antibody production significantly by oral administration or intraperitoneal inoculation. When mice are immunologically suppressed by cyclophosphamide and then receive antigen together with pyran, their antibody titers are as high as non-immunologically suppressed ones'. In other words, Pyran can relieve the immunosuppression exerted by cyclophosphamide. The finding suggests that Pyran may be of value in reducing microbial infection in patients who received immunosuppressive antineoplastic agents.

Adjuvants, Immunologic↗
PubMed1976

Specific potentiation of L1210 vaccine by pyran copolymer.

Pyran copolymer (NSC 46015) was found to potentiate strongly the immune response of C57BL/6J X DBA/2 F1 mice to 10(4) live L1210 tumor cells following suboptimal vaccination with 10(7) radiation-inactivated L1210 cells. Optimal immunity to challenge was produced by concomitant i.p administration of pyran and L1210 vaccine, and activity was dependent upon both pyran and vaccine dosages. In addition, this immunopotentiation seemed to be related to the intrinsic viscosity of different pyran preparations tested, although all the pyran compounds had significant activity. Furthermore, the increased immunity of subsequent live tumor challenge appeared to be specific for the vaccinating cell type.

Animals↗