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Biomedical subjects

C Chany

Publications and source records attributed to C Chany.

At least 19 recordsLinked to original sources
PubMed1992

Enhancement by stable butyrate derivatives of antitumor and antiviral actions of interferon.

The use of n-butyric acid has been associated with induction of cell differentiation and bypassing of genetic defects in the suppression of malignancy. This biological response modifier satisfies the requirements for specificity and low toxicity, and its use can be considered as an alternative approach to conventional cancer chemotherapy. However, a lack of clinical efficacy has been observed with butyrate and attributed mainly to the rapid metabolism of the compound. Butyric acid pro-drugs derived from monosaccharides such as 3-O-butanoyl-1,2-O-isopropylidene-alpha-D-glucofuranose (MAG = 3but) have consequently been devised. Pharmacokinetic and biological advantages of MAG = 3but have been previously described. In the present report, we have studied the effect of MAG = 3but on murine interferon-alpha, beta (IFN) anticellular, antitumor and antiviral activities. In vitro, it appears that MAG = 3but predisposes malignant MSV cells to a later, complete establishment of the antiproliferative and the cell-differentiating effects of IFN, and the antiviral action of the latter in the same line of cells infected with encephalomyocarditis (EMC) virus. In vivo, combined treatment with MAG = 3but and IFN protects mice effectively against the fatal development of ascitic sarcoma 180 TG and the lethal effect of EMC virus infection.

Animals↗
PubMed1992

[Protective activity of monoacetone glucose 3-butyrate, prodrug of n-butyric acid, against the fatal effect of encephalomyocarditis virus in mice].

A comparative study was made, in the mouse, on antiviral properties of a prodrug of n-butyric acid derived from monosaccharides: monoacetone glucose 3-butyrate (MAG = 3but), and of a free form of n-butyric acid: arginine butyrate (BuO Arg). Preventive injection of MAG = 3but protected the mice twice as effectively as BuO Arg against the lethal effect of 100 LD50 of encephalomyocarditis virus. Under the same experimental conditions, monoacetone glucose (MAG) used as carrier of the biologically active moiety, was inactive on its own. Antiviral activity of MAG = 3but was shown not to be virucidal, but rather could involve stimulation of the immune system. This capability supplements known anticellular and antitumoral properties. In total these results indicate a prime therapeutic importance for this new molecule, pharmacokinetically suitable, with its very low toxicity, for clinical application. Combined use of MAG = 3but with biological response modifiers which have similar affinity, such as Interferon, is discussed.

Animals↗
PubMed1991

Butyric monosaccharide ester-induced cell differentiation and anti-tumor activity in mice. Importance of their prolonged biological effect for clinical applications in cancer therapy.

The interest of butyric salts is based on their capacity to promote differentiation of malignant cells and inhibition of tumor development. The phenotypic modifications are rapidly reversible and require the continuous presence of butyric salts in the target area, which raises problems for therapeutic applications. We show here that the covalent binding of n-butyric acid on natural polyhydroxylated compounds such as monosaccharides, especially 3- or 6-O-butanoyl-1,2-O-isopropylidene-alpha-D-glucofuranose, retains the majority of the biological properties of n-butyric acid. The delayed degradation of these covalent compounds is associated with an improved maintenance of cell differentiation and anti-tumor protection in mice. These butyric complexes thus seem potentially useful for therapeutic applications.

Animals↗
PubMed1991

Pharmacokinetics of butyric acid derivative with xylitol.

The short chain fatty acids, especially butyric acid salts have interesting biological properties. In some cases, transformed cells can recover a normal phenotype and in animal, butyrate salts increase antitumor resistance. Butyrate may be considered as possibly useful for antitumor therapy. But these products exhibit two essential disadvantages which restrict their clinical use in man: high concentrations required to achieve therapeutic effects and rapid excretion with short half life. In order to optimize the clinical use of butyrate, we studied a n-butyric acid ester obtained with xylitol selected for its physiological and metabolic inertia. Structure determination of tributyryl xylitol was carried out by mass and NMR spectrometry (MW = 344). The low toxicity and the antitumor effects of this ester, especially in association with Corynebacterium parvum and interferon, confirm its therapeutic interest. The slow excretion of this prodrug should make butyrate clinical use easier by preventing extensive systemic metabolism and metabolic side-effects due to cations of butyrate salts.

Animals↗
PubMed1990

Anti-tumor protection induced in mice by fatty acid conjugates: alkyl butyrates and poly(ethylene glycol) dibutyrates.

Simple fatty acids, especially butyrate salts, have interesting biological properties, since they are able to down-regulate cell growth and promote various differentiated cellular functions. Their use for anti-tumor treatment is, however, hampered by their over-rapid diffusion in the blood, followed by a short-lived biological action. We have therefore devised conjugates linking butyrate with either (i) aliphatic alcohols of increasing carbon numbers ranging from C4 to C12 or (ii) poly(ethylene glycols) of increasing molecular weights. In both cases, the resulting butyric esters can be hydrolysed by esterases which can release biologically active subunits from the synthetic compounds. As shown in the present study, only one conjugate in each series gave satisfactory anti-tumor protection: namely, I-octyl butyrate and poly(ethylene glycol 1000) dibutyrate respectively. A single immune-stimulatory injection of purified Corynebacterium parvum extract prior to administration of the conjugates significantly increased the anti-tumor potency.

Adjuvants, Immunologic↗
PubMed1990

Sarcolectin and interferon in the regulation of cell growth.

Sarcolectin is an endolectin present in a great variety of conjunctival tissues (muscles, cartilage, sarcomas), but also in brain or placental extracts of vertebrates, including primates. When purified to electrophoretical homogeneity as a 65-kd protein, it agglutinates cells and has an affinity for simple sugars. In addition, it is able to inhibit the synthesis of interferon (IFN)-dependent secondary proteins and to restore cells to their status ad primum. The biological effect of Poly(I).Poly(C)-induced feedback interferon is inhibited by the addition of sarcolectins, which also abolishes cellular refractoriness to repeated IFN induction. Similarly, sequential association of, first, Poly(I).Poly(C); 4-5 h later, sarcolectin restores the full capacity of both to promote cell growth, unrestrained by IFN. Indeed, the secondary proteins which are in the process of being synthesized are inhibited. In a great variety of animal cells, sarcolectin can also initiate growth after it has been blocked by IFN. This is not an all-or-none effect, but a balance may be struck by IFN and sarcolectin, depending on their respective concentrations and specific activity. We propose that the coordination of these cellular functions of Poly(I).Poly(C), IFN, and sarcolectin takes place in the form of a triangular growth-regulatory cycle and postulate that they thus maintain a balance during differentiated normal tissue development.

Animals↗
PubMed1990

Mechanism of homeostatic regulation of tissue growth and reversion of transformed cells to nonmalignancy: a yin-yang problem.

The regulation of coordinated cell growth and the development of malignancy are phenomena that are too complex to be accommodated in a narrow frame. However, on the basis of about 30 years experience with interferon and the analysis of the literature presently available, it can be suggested that: (i) normal growth is discontinuous, promoted by various growth factors; (ii) its development is downregulated by a great variety of alpha/beta interferons, which are easy to detect in rapidly growing tissues during the fetal period. Arrest of the cells in interphase could promote the expression of genetically programmed differentiation; (iii) recycling of growth is obtained by sarcolectins able to downregulate the cellular effects of interferons and to relaunch cell multiplication. To maintain harmonious growth, the synthesis and the effect of these proteins have to be in equilibrium. In transformed cells, after prolonged treatment with IFN (acting as an antioncogene), v-mos, beta interferon, and sarcolectin are continuously expressed and stay in balance. This could explain in part the stable reversion to nonmalignancy, under conditions that are reminiscent of the ancestral "Yin-Yang" principle. The review presented here is restricted to the inteferon system, whose importance in coordinated growth regulation is presently poorly defined. It can be judged, however, probably significant because of the great number of alpha isoforms existing in addition to IFN-beta, which are responsible for the activation of a number of more or less defined secondary proteins; each of these could have a more specific biological role as regards the great number of growth factors and promoters.

Animals↗
PubMed1989

Unusually large interferon-alpha-like mRNAs and high expression of interleukin-6 in human fetal annexes.

Endogenous interferons (IFNs) with antiviral activity have been detected in human fetal annexes, without any apparent induction. Some are of unusually high molecular weight and antigenic properties (Duc-Goiran P., Robert-Galliot, B., Lopez, J., and Chany, C. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 5010-5014). We study here the expression of IFN genes from the three antigenically distinct groups, in placental tissues taken during third-trimester pregnancies. We show by Northern blot analysis with RNA probes that IFN-alpha-like transcripts correlate with the presence of functionally active protein, purified by immunoaffinity chromatography. We fractionate on a formamide sucrose gradient, identify, and characterize a large 4.3-kb IFN-alpha-like transcript, which may be specifically expressed during fetal development. Despite the absence of IFN-beta transcript, a protein with an antiviral activity which was neutralized with a polyclonal anti-IFN-beta serum was detected in the placenta and could be related to a beta-like IFN. Besides IFNs, various growth factors and cytokines can be found in the placenta. We report here the presence of interleukin-6 expressed at high levels in fetal annexes. The coexpression of Interleukin-6 and endogenous IFNs suggests that they play an important role during development.

Amnion↗
PubMed1989

Pharmacokinetic study of butyric acid administered in vivo as sodium and arginine butyrate salts.

Considering that butyrate-treated malignant cells can recover in a transitory fashion a non-cancerous phenotype, the authors carried out a pharmacokinetics study of butyric acid injected as sodium or arginine salts for possible antitumor therapies. In the case of 1-14C-labelled butyrate, the appearance of radioactivity in the blood of injected mice is rapid and some of it is maintained for relatively long periods in different organs, mainly the liver. However, no precision can be given about the structure of radioactive compounds in blood and tissues. Using gas-liquid chromatography, the authors studied the metabolism of butyrate in both animals and man. In mice and rabbits, the half-life is less than 5 min. In man, the butyric acid elimination curve can be divided into two parts corresponding to two half-lives: for the first (0.5 min), the slope suggests an accelerated excretion, while for the following (13.7 min), a slow plateau is observed. The rapid elimination of butyrate is a limiting factor for practical applications. However, the lack of toxicity supports its use in human therapy.

Adult↗
PubMed1989

Presence of a constitutive paracrine beta-interferon in v-mos-bearing nonmalignant reverted cells.

A stable nonmalignant revertant cell line was derived from Moloney murine sarcoma virus-transformed BALB/c cells after long-term cultivation in the presence of murine type I interferon (IFN). These cells gradually established resistance to exogenous IFN and were also seen to contain IFN-dependent proteins. The presence of an endogenous IFN was confirmed by the results of Northern blot analysis and in situ hybridization with an IFN-beta probe, showing that only mRNA specific for IFN-beta- could be found in the uninduced reverted cells. The latter synthesized only a small amount of IFN-beta protein and exhibited few IFN-specific membrane receptors, which bound recombinant IFN-beta with a high affinity. After treatment with IFN antibody, the overexpression of H-2 major histocompatibility antigen genes was significantly down-regulated. These findings strongly suggest the existence in this reverted cell line of a constitutive IFN which, acting through an autocrine and/or paracrine mechanism, might play a role in maintaining the reverted state.

Animals↗
PubMed1988

Interferon- and sarcolectin-dependent cellular regulatory interactions.

Interferons, via specific membrane-bound receptors, induce various cellular functions of which antiviral protection is the most extensively studied. We have previously reported the existence of interferon antagonists (referred to as sarcolectins) in various tissue extracts from placental blood, cartilage, brain, muscle, or from sarcomas. These sarcolectins have been fully characterized and purified to homogeneity. In interferon-treated cells, they restore virus sensitivity 4-6 h after the establishment of antiviral protection. In the present study we investigate the effect of sarcolectins on the steady state levels of two double-stranded RNA dependent enzymes, 2-5A (p chi (A2'p)nA) synthetase and protein kinase. Several authors have previously emphasized the role of these enzymes in the mechanism of interferon's antiviral action. Interferon promotes a 4-8 fold increase in protein kinase and 2-5A synthetase in cells. Addition of sarcolectin 5 h after interferon results in a dramatic reduction in the steady state levels of both these enzymes, as shown by their decreased activity and yield observed in Western blot assays. The degradation of the antiviral response in sarcolectin-treated cells might therefore be at least partially attributed to a reduced synthesis of protein kinase and 2-5A synthetase. Since there are no direct interactions between sarcolectins and interferon or its receptors, it can be postulated that sarcolectins exert their effect through these interferon-dependent proteins. We postulate that the opposing biological effects of interferon and sarcolectins strike a balance which may, however, be modified in one direction or the other, depending on their respective concentrations.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Detection of vesicular stomatitis virus (VSV) RNA in the central nervous system of infected mice by in situ hybridization.

Using in situ hybridization with a cloned DNA probe specific for the VSV G protein, viral RNA was detected and localized in CNS tissue of mice infected i.c. with either wild or ts G 31 VSV mutant. In both cases, brain and spinal cord neurons were the only cells seen to contain viral RNA. Virus-positive neurons were observed enclosed in spongious areas induced by the ts VSV mutant. These results suggest that the VSV shows a strong tropism for the neuronal cell and indicate that the vacuole formation might be associated with the expression of the VSV G protein gene in infected neurons.

Animals↗
PubMed1987

Cell distribution and antigenic properties of mammalian sarcolectins.

Sarcolectins are present in a great variety of tissues from mammalian origin. Such substances were observed to be secreted from cultures of human embryonic fibroblasts, human osteosarcoma and rat Rous sarcoma transformed cells and could be extracted from TG 180 Crocker Sarcoma or normal human placenta. All sarcolectins tested here, were comparable by their physicochemical properties to those previously reported in hamster or human sarcomas. Indeed, they are proteins or glycoproteins, resistant to pepsin and migrate in SDS-PAGE in the 65 kDa area. They agglutinate cells with an affinity for simple sugars and degrade previously established interferon-induced antiviral resistance. Considering the hamster sarcolectin as reference in this comparative study, both differences and similarities in the antigenic properties of mouse, rat and human sarcolectin variants were demonstrated. An indirect immunofluorescence assay showed that sarcolectins were specifically labelled on the cell surface but not detected in the cytoplasm after methanol or acetone permeabilization of the membrane. By electron microscopy, using immunoperoxidase labelling, sarcolectins can be localized on the surface of normal, transformed, human or rat cells. Only limited segments of normal cell membranes were labelled, while transformed cells were frequently stained on their whole surface. Other known extracellular proteins, such as fibronectin and collagen, did not share common antigenic determinants with sarcolectins.

Animals↗
PubMed1986

Aspartate-assisted immune stimulation: its importance in antitumor and antiviral protection.

Immune stimulators such as Corynebacterium parvum (CP) are useful for antitumoral and antiviral therapy. However, the immune trigger cannot be reactivated without adversely affecting the disease. We have tried to amplify the results yielded by a single injection of CP by using either interleukin-2 (IL2) or aspartate salts (ASP). In the present report, we show that IL2 has no detectable clinical effect. In contrast, the addition of an ASP salt increases the antiviral and antitumoral protection afforded by the CP-induced trigger. Moreover, treatment using only ASP slightly protects against tumor development and significantly increases antiviral resistance during experimental encephalomyocarditis (EMC) infection. This ASP-assisted CP immune stimulation improves antitumoral resistance even when ascitic tumors have already developed. In the latter case, tumor regression can even be detected. Since ASP increases T-cell cytotoxicity in vitro and aggravates spontaneous T-cell lymphomas in AKR mice, the involvement of T-cell-mediated immunity may explain antitumoral and antiviral effects. We propose the use of this therapeutic model for human cancer therapy, and possibly for treating AIDS.

Adjuvants, Immunologic↗
PubMed1986

Role of VSV G antigen in the development of experimental spongiform encephalopathy in mice.

The ts G31 VSV mutant induced spongiform encephalopathy without any inflammatory response when injected i.c. into the mouse. In electron microscopy, no virions could be detected in spongiform lesions. In contrast, with the wild VSV strain inflammatory lesions were seen, which contained viral particles in great abundance. As previously shown in vitro, when using the ts G 31 mutant at the nonpermissive temperature, the G antigen can spread from membrane to membrane to distant sites, fusing a great number of cells even in the absence of virus multiplication. Therefore, we postulate that a comparable mechanism is responsible for extensive brain lesions originating probably from a relatively small number of G antigen-producing cells. Indeed, the spongious regions seen mainly in the grey matter contained vacuoles, whose walls were clearly stained by peroxidase-labelled immune serum to G antigen, without detectable virions or inflammatory lesions. The vacuoles probably represent altered and swollen dendritic cell membranes. The relationship between spongiosis development and antigen diffusion in the absence of significant virus replication is discussed.

Animals↗