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N C Phillips

Publications and source records attributed to N C Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1988

Tumor-associated antigens as immunotherapy targets.

The potential of liposomes to act as immunoadjuvant carriers of tumor-associated antigens (TAA) has been investigated. The incorporation of B16 melanoma TAA within liposomes resulted in immunological recognition by non-tumor-bearing mice, and subsequent inhibition of tumor growth upon tumor challenge. The immunogenicity and protective activity were enhanced by the concomitant incorporation of a lipophilic immunoadjuvant, MDP-GDP, in the liposome preparation. The ability of liposomal preparations to augment the immunogenicity of a human oncofetal antigen, CEA, was also studied. The incorporation of CEA within liposomal carriers resulted in immunological recognition in mice at doses (0.1 micrograms) significantly less than required in Freund's complete adjuvant (25 micrograms), maximal responsiveness being found with liposomal-CEA-MDP-GDP preparations. Liposomal TAA vaccines may therefore require the presence of immuno-adjuvant-active agents for the induction of effective immunological responses in individuals at risk from recurrent disease.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Anti-infectious activity of liposomal muramyl dipeptides in immunodeficient CBA/N mice.

Two muramyl dipeptides, N-acetylmuramyl-L-alanyl-D-isoglutamine and its adjuvant-inactive isomer N-acetylmuramyl-D-alanyl-D-isoglutamine, were examined for their ability to protect mice carrying the CBA/N immune deficiency gene (xid) against lethal bacterial challenge. Prophylactic treatment with N-acetylmuramyl-L-alanyl-d-isoglutamine gave significant protection against Streptococcus pneumoniae, Salmonella typhimurium, and Salmonella enteritidis infection. N-Acetylmuramyl-D-alanyl-D-isoglutamine was unable to confer protection. Incorporation of the lipophilic glycerol dipalmitate derivatives of the two muramyl dipeptides within liposomal carriers resulted in a significant enhancement of anti-infectious activity, both with respect to number of survivors and length of survival. Liposomal muramyl dipeptides were 10- to 15-fold more potent than free muramyl dipeptide; enhanced potency was most evident with N-acetylmuramyl-D-alanyl-D-isoglutamine. Prophylactic treatment with liposomes containing the lipophilic muramyl dipeptides resulted in enhanced clearance of bacteria from the blood (greater than 3-fold increase in rate) when compared with that of hydrosoluble N-acetylmuramyl-L-alanyl-D-isoglutamine, indicating a correlation between reticuloendothelial stimulation and anti-infectious activity.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Liposomal incorporation and immunogenicity of carcinoembryonic antigen.

The ability of liposomal carriers to act as immuno-adjuvants for carcinoembryonic antigen (CEA) has been evaluated. Liposomal incorporation was consistent with association with the aqueous phase of the liposome, little if any of the protein being associated with the phospholipid bilayer. The incorporation of CEA within liposomal carriers resulted in immunological recognition in mice at doses (0.1 microgram) significantly less than required in Freund's complete adjuvant (25 micrograms), maximal responsiveness being found with liposomal-CEA preparations containing a lipophilic immunoadjuvant, N-acetyl-muramyl-L-alanyl-D-isoglutamyl-glyceryl-dipalmitate. Such liposomal formulations may have utility as immunoadjuvants for cancer immunotherapy.

Adjuvants, Immunologic↗
PubMed1987

Induction of murine macrophage tumoricidal activity and treatment of experimental pulmonary metastases by liposomes containing lipophilic muramyl dipeptide analogs.

The ability of three members of a new class of lipophilic muramyl dipeptide derivative to induce murine macrophage tumoricidal activity after liposomal incorporation was investigated. Liposomes containing the glycerol dipalmitate (GDP) derivatives of N-acetylmuramyl-L-alanyl-D-isoglutamine, N-acetylmuramyl-L-alanyl-D-glutamine-n-butyl ester, and N-acetylmuramyl-D-alanyl-D-isoglutamine were 5000, 2000, and greater than 10,000-fold more potent than the free muramyl dipeptides in inducing peritoneal macrophage tumoricidal activity in vitro. In situ activation of peritoneal macrophage tumoricidal activity showed that liposomal muramyl dipeptide-GDP derivatives were more potent than free hydrosoluble or sonicated muramyl dipeptide-GDP preparations. In situ induction of alveolar macrophage tumoricidal activity after i.v. treatment was observed with liposomes containing muramyl dipeptide-GDP derivatives, but not with hydrosoluble or sonicated lipophilic derivatives. Liposomes containing muramyl dipeptide-GDP derivatives were therapeutically active against experimentally induced pulmonary B16 melanoma tumors in C57BL/6 mice. These results demonstrate that when incorporated within liposomes this class of lipophilic muramyl dipeptide derivative is a potent inducer of macrophage tumoricidal activity both in vitro and in situ, and possesses antitumor activity in therapeutic treatment protocols.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

In vitro inhibition of murine B-cell tumor growth by MDP, MDP(D-D) and Vaccin is mediated by macrophages.

The effect of two muramyl dipeptides, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and N-acetylmuramyl-D-alanyl-D-isoglutamine (MDP(D-D)), on the in vitro growth of two murine ascitic plasmacytomas, MOPC 173 and TEPC 15, and on an ascitic lymphoma cell line, ABPL2, was studied. The ability of the muramyl dipeptides to inhibit tumor cell growth was compared with a sonicated antigenic preparation of Mycobacterium vaccae (Vaccin), known to have macrophage stimulation activity. The growth of all three ascitic cell lines was inhibited by both muramyl dipeptides and Vaccin. Macrophage-depletion of the ascitic cell populations led to an increase in cell growth of TEPC 15 and MOPC 173, and a decrease in ABPL2. A reduction or loss of the inhibitory activity of the muramyl dipeptides or Vaccin was also observed, and no inhibitory activity was found when the tumor cell lines were cultured in vitro to render them macrophage-free. The inhibitory activity of MDP or MDP(D-D) was restored when purified ascitic macrophages were added to the in vitro cultured cell lines. It was demonstrated that a minimum number of macrophages were necessary for the expression of inhibitory activity. Indomethacin, a PG-synthetase inhibitor, was found to act in a synergistic manner with MDP and MDP(D-D) in inhibiting TEPC 15, but antagonized the effect of these two agents on ABPL2. The lymphoma cell line ABPL2 appeared to be the most sensitive to inhibition by MDP(D-D), a nonpyrogenic, adjuvant-inactive stereoisomer of MDP.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Activation of alveolar macrophage tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative.

The ability of a member of a new class of lipophilic muramyl dipeptide (MDP) derivative, muramyl dipeptide-glyceryldipalmitate (MDP-GDP), to induce alveolar macrophage cytotoxic activity in vitro towards B16 melanoma cells when incorporated into two types of liposome was studied. MDP-GDP incorporated into conventionally prepared liposomes formulated from distearoylphosphatidylcholine and phosphatidylserine (7:3 molar ratio) was 10-fold more effective than liposomes containing MDP, and 7000-fold more effective than free MDP in inducing macrophage cytotoxic activity. MDP-GDP incorporated into freeze-dried liposomes was 50,000- to 100,000-fold more effective than free MDP in inducing such activity. Freeze-dried liposomes containing MDP-GDP were efficiently localized in the lungs of normal mice, and induced cytotoxic activity in the alveolar macrophages. Such liposomes were able to significantly reduce the pulmonary metastatic burden of mice carrying the B16 melanoma. These data provide evidence that this class of lipophilic MDP derivative, when incorporated into freeze-dried liposomes, is a potent inducer of macrophage cytotoxic activity in vitro and in situ, and has antitumor activity in vivo. In addition, the use of a freeze-drying procedure allows the preparation and long-term storage of reproducible liposome formulations.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Activation of macrophage cytostatic and cytotoxic activity in vitro by liposomes containing a new lipophilic muramyl peptide derivative, MDP-L-alanyl-cholesterol (MTP-CHOL).

The ability of liposomes containing a new lipophilic muramyl peptide derivative, MDP-L-alanyl-cholesterol (MTP-CHOL), to induce peritoneal macrophage cytostatic activity and alveolar macrophage cytotoxic activity toward tumor cell targets in vitro was determined. MTP-CHOL was shown to be efficiently incorporated and subsequently retained in distearoylphosphatidylcholine/phosphatidylserine liposomes (DSPC/PS; 7:3 molar ratio), whereas hydrosoluble muramyl dipeptide (MDP) was rapidly lost due to leakage. Liposomes containing MTP-CHOL were able to stimulate mouse peritoneal macrophage cytostatic activity under conditions where free MDP was without effect. MTP-CHOL incorporated into liposomes was approximately eightfold more effective than liposomes containing entrapped MDP and 7,400-fold more effective than free MDP in inducing rat alveolar macrophage cytotoxic activity. These results provide evidence that the coupling of MDP to a lipophilic molecule, cholesterol, results in the formation of a viable liposome formulation that is a potent inducer of macrophage-mediated antitumor activity.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Modulation of the growth of murine thymoma cell lines having different Lyt-phenotypes by MDP and MDP(D-D): macrophage-mediated inhibition of in vitro cell growth.

The ability of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and its adjuvant-inactive stereoisomer, N-acetylmuramyl-D-alanyl-D-isoglutamine, (MDP(D-D] to inhibit the in vitro growth of 3 murine ascitic thymoma lines, expressing different Lyt-phenotypes, was studied. MDP inhibited the growth of all 3 cell lines. MDP(D-D) inhibited the 2 cell lines expressing Lyt-1+2- or Lyt-1+2+ phenotypes, but not the third cell line which expressed the Lyt-1-2+ phenotype. The ability of MDP or MDP(D-D) to inhibit thymoma growth was lost when the ascitic cell populations were depleted of macrophages. MDP could be replaced by a supernatant derived from an ascitic Lyt-1+2- cell population exposed to MDP. The supernatant required the presence of macrophages for activity. The inhibition by MDP of the growth of the Lyt-1-2+ cell line was prostaglandin synthetase dependent: indomethacin antagonized the inhibitory activity of MDP. The inhibition by MDP of the Lyt-1+2- cell line was partially antagonized by indomethacin, and no antagonism was observed with the Lyt-1+2+ cell line.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Substituted (2-phenoxyphenyl)acetic acids with antiinflammatory activity. 2.

A number of polychlorinated (phenoxyphenyl)acetic acids were prepared as close structural analogues of the antiinflammatory compound fenclofenac, [2-(2,4-dichlorophenoxy)phenyl]acetic acid. Increased potency was shown in several of these compounds, in particular, [2-(2,3,5,6-tetrachlorophenoxy) phenyl]acetic acid (8), which was 40 times more potent than fenclofenac in the adjuvant-induced arthritis screen. In further tests it was found to be equipotent with indomethacin but with a much reduced incidence of acute toxicity (LD50 and ulcerogenicity). On chronic dosing, however, serious toxicity problems arose (including anemia, neutrophilia, and severe peritonitis), and this led to the abandonment of further work on the compound. Three further analogues were prepared containing NH, S, and SO moieties bridging the phenyl rings. Although the NH compound bore a very close structural resemblance both to the above O-linked compound and the potent antiinflammatory drug diclofenac, [2-[(2,6-dichlorophenyl)imino]phenyl]acetic acid, it showed low activity in primary screens. Similarly, neither the S- or SO-bridged analogues had potencies that approached that of 8.

Animals↗
PubMed1982

Exacerbation of experimental poly-D-lysine arthritis by C-reactive protein.

Rabbit C-reactive protein (Cx-rp) was able to induce a prolonged exacerbation of inflammation when injected locally into arthritic rabbit knee joints. The increase in the level of inflammation, measured as the change in joint temperature, was accompanied by an increase in serum Cx-rp levels. Locally administered Cx-rp had no effect on joint swelling. Cx-rp, when injected locally into normal knee joints, had no effect on temperature or swelling. Cx-rp was unable to induce its own synthesis when injected intravenously into normal rabbits. The findings support a role for Cx-rp as a positive modulator of acute inflammation.

Animals↗
PubMed1981

Treatment of experimental poly-D-lysine arthritis in rabbits by non-steroidal anti-inflammatory compounds.

The effect of five non-steroidal anti-inflammatory compounds on experimental poly-D-lysine arthritis in the rabbit knee joint have been determined. Two non-invasive methods of assessing the inflammation, measurement of swelling and temperature have been used to follow the effect of treatment. The rank order of potency for the reduction of temperature was indomethacin greater than flurbiprofen greater than diclofenac sodium greater than sulindac greater than fenclofenac. Reduction in joint temperature was shown not be be due to vasoconstrictor effect. Reduction of swelling was variable and not dose-related. The method described allows the activity of such compounds on experimental articular arthritis to be determined rapidly.

Animals↗
PubMed1979

Monitoring of experimental arthritis in rabbits.

The effect of ambient temperature and air flow on the radiometric measurement of experimental arthritis in rabbit knee joints has been studied. Temperature changes due to inflammation in such joints could be detected up to 70 days after induction of the arthritis by the use of radiometry. The method has been used to quantitate the anti-inflammatory activity of intra-articularly injected cortisol acetate and orally administered aspirin. It is suggested that this method of noninvasive monitoring has a number of advantages over other procedures.

Animals↗
PubMed1979

Liposome-incorporated corticosteroids. II. Therapeutic activity in experimental arthritis.

The anti-inflammatory activity of liposomes containing cortisol palmitate was determined in experimental acute arthritis in the rabbit knee by measuring joint temperature and diameter. The therapeutic activity of the liposome preparation was dose-dependent for both these parameters of inflammation. Liposomal corticosteroid therapy was effective also in decreasing the joint temperature of an acute inflammatory 'flare' superimposed on an underlying chronic arthritis. Phosphatidic acid was necessary for expression of full anti-inflammatory activity of the liposome preparation.

Animals↗
PubMed1979

Liposome-incorporated corticosteroids: I. The interaction of liposomal cortisol palmitate with inflammatory synovial membrane.

Cortisol palmitate-containing liposomes were stable in rheumatoid synovial fluid at 37 degrees. Two hours after the intra-articular injection of such liposomes into experimentally arthritic rabbits relatively high proportions of the steroid and lecithin components were recovered from the synovialis. The level of cortisol in the tissue at this time was inversely related to the chronicity of the inflammation. It was found also that the degree and duration of the anti-inflammatory activity of the liposomes was greatest in the initial acute phases of the inflammation.

Animals↗
PubMed1978

Characterization of the mutant alpha-mannosidase in bovine mannosidosis.

Residual acidic alpha-mannosidase, varying in amount up to approx. 15% of normal values, can be measured in various organs of a calf with mannosidosis. The highest specific activity and relative proportion of residual activity were found in the liver. Chromatography on DEAE-cellulose showed that the residual activity was associated with two components, which were eluted at comparable positions with those found in normal tissues. The residual activity had a lower thermal stability and a higher K(m) value for a synthetic substrate than did the normal enzyme. No differences in molecular weight or electrophoretic mobility between normal acidic alpha-mannosidase and the residual activity were observed by gel filtration and electrophoresis on cellulose acetate respectively. The isoelectric focusing profiles for the alpha-mannosidase in the normal and pathological livers were very similar. It is suggested that a mutant enzyme, resulting from a mutation in a structural gene, accounts for the residual acidic alpha-mannosidase in mannosidosis. The mutant enzyme, which cross-reacts with antiserum raised against normal bovine acidic alpha-mannosidase, is present at a decreased concentration compared with the normal enzyme. There is a correlation between the concentrations of residual activity and cross-reacting material in mannosidosis. alpha-Mannosidase with a pH optimum of 5.75 and which is activated by Zn(2+) was also detected in the liver of the calf with mannosidosis. However, it is probably not a product of the defective gene because addition of Zn(2+) indicated that it was also present in normal tissues.

Animals↗