The biological activities of mannans and related complex carbohydrates
Ian R. Tizard, BVMS, PhD, Robert H. Carpenter, DVM, MS, t Bill H. McAnalley, PhD and Maurice C. Kemp, P
Department of Veterinary Microbiology and Parasitology, College of Veterinary Medicine. Texas A&M
University, College Station, TX, and t Carrington Laboratories, Inc. Irving, TX, USA
Complex polymers containing mannose (mannans) possess significant biological activity when administered to mammals. When given orally, they
inhibit cholesterol absorption and induce hypocholesterolemia. If administered by other routes, they bind to mannose-binding proteins and induce
macrophage activation and interleukin-l release, inhibit viral replication, stimulate bone marrow activity, promote’ wound healing, and inhibit tumor
growth. This range of activities makes the mannans potentially important biological-response modifiers and therapeutic agents.
Keywords: Mannans, macrophages, tumors, cholesterol
Introduction
Galactomannans, in the form of plant gums, have long been used
as food additives. Derived from the endosperm of leguminous
seeds, they arc widely used as binders or for the control of texture.
Recently, these gums, as well as certain other mannans, have been
ascribed significant physiologic or therapeutic proper- ties.i For
example, there has been a tradition in Japanese folk medicine that
extracts of certain fungi have anticancer activity. On
investigation, many of these extracts have been found to contain
complex
carbohydrates
with
immune-stimulating
and
antineoplastic activity. These carbohydrates are usually polymers
of
glucose
(glucans),
mannose
(mannans),
xylose
(hemicelluloses), or fructose (levans), or are mixtures of sugars.
The individual sugars may be bonded in different ways and the
chains may be branched or unbranched. Glucans have been the
most widely studied of these immunostimulatory carbohydrates,
but it has become increasingly clear that mannans are equally, if
not more, effective in this respect. Pure rnannans are relatively
uncommon in higher plants, although they are a major structural
component of some yeast. For example, approximately 45% of the
cell wall of Saccharomyces cerevisiae consists of a mannan, This
mannan is a water-soluble molecule composed of α-(l,6)-, α(1,3)-, and α-(l,2)- linked, partially phosphorylated D-mannose
residues.2 The mannan found in the cell wall of Candida utilis is
an α-(1,3) - linked molecule with, an average relative molecular
mass (Mr) of 1 x 103 d.3,4 The mannan of Candida albicans
_____________________
Address reprints requests to Dr. Ian R.Tizard Department of
Vetinerary Microbiology and Parasitology, College of Veterinary
Medicine, Texas A&M University, College Station, TX 771.43,
USA. Accepted for publication August 21, 1989
290
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Mol. Biother., 1989, vol. 1, No, 6
is a highly branched molecule with short chains of α - (1,2)-linked
mannose residues joined together by α-(1.6) linkages5 and bound
to small peptides.6 Methylated mannans are major components of
Coccidioides irnmitis cell walls, whereas a mannan with β-(l, 3)
and β - (1, 4) bonds is found in the fungus Rhodotorula rubra.7
The leaf of the aloe vera plant (Aloe Barbadensis) contains large
amounts of acemannan, a β- (1, 4)-linked acetylated mannan of
approximately l000kd.8
Much more abundant than pure mannans are the mixed glucosemannose polymers: glucomannans. Glucomannans have physical
properties similar to those of cellulose and are found, therefore, in
plant and fungal cell walls associated with celluloses. The β-(1,4)
- linked linear glucomannans are a major component of the
hemicellulose fraction of the secondary cell wall of gymnosperms,
but are present only in minor amounts in cell walls of
angiosperms.9 One of the most interesting of the glucomannans is
found in Konnyaku powder, a popular food source in Japan. 10
Konnyaku powder is obtained by grinding tubers of the potatolike plant Amorphophallus konyac. The powder consists largely
of a water-soluble glucomannan called Konjac mannan. Konjac
mannan is a β-(1, 4) - molecule in which sequences of three
mannose units separate the glucose units. The molar ratio of
glucose to mannose in Konjac mannan is 1:1.6.11,12 The molecule
is O-acetylated with one acetyl group per six glucosyl residues,
and this ratio may have a significant bearing on its biological and
physical properties. Another important glucomannan is that
derived from the fungus Microellobosporia grisea. This molecule,
called DMG, consists of a straight β - (l,4) glucan chain with
single α-mannosyl groups tagged to alternate glucosyl residues by
α1,3 and a α 1,6 bonds.13,14
Galactomannans copolymers of galactose and mannose are
found in seeds such as coffee, locust, guar, and soy beans. These
seed galactomannans arc usually based on a β-(l, 4) mannan
backbone solubilized with short ἀ-(l, 6) - linked galactose side
chains. Seed galactomannans may be used as gums, such as guar
gum (mannose to galactose ratio, 2: 1) or locust gum (mannose to
galactose ratio, 3 to 6: 1), and are incorporated in many foods as
texture modifiers and as binders.
Mannans (including the galactomannans and glucomannans) are
relatively resistant to attack by mannosidases but can be degraded
by exomannanases and endomannanases.15-20 Betamannanases
have been isolated from wood-rotting bacteria, from human gastrointestinal bacteria, from rumen streptococci, from some seeds,
and from arthropod digestive juice.20
Effects of Mannans on Intestinal Function
Konjac mannan, like other mannans, forms a viscous gel when
mixed with water. This gel causes a number of interesting effects
when incorporated in the diet. These include reductions in
appetite, glucose absorption, and cholesterol absorption.
Thus, treatment of overweight hypertensive patients with oral
Konjac mannan, with or without reduced calorie intake, decreases
body weight.21 Total plasma cholesterol and triglycerides were
lowered in patients treated with this substance, and it was speculated that the weight loss was probably due to satiation as a result
of filling of the intestine with mannan gel.
When ingested, Konjac mannan gel significantly slows glucose
absorption from the intestine.10 For this reason, Konjac mannan
has been used to treat “dumping syndrome,” a result of
postprandial hypoglycemia that occurs in patients who have had
surgical gastrectomy. Because food passes through their stomach
at an accelerated rate, these patients have unusually rapid glucose
absorption. Consequently, they initially develop hyperglycemia to
which they respond with hyperinsulinemia; this in turn rapidly
causes severe hypoglycemia. Addition of only 2.6 to 5.2 g of
Konjac mannan to a carbohydrate-rich meal slowed the
postprandial increase in plasma glucose. When added to the diet
of patients with previous gastric surgery, Konjac mannan
decreased the postprandial in crease in plasma insulin, preventing
the development of hypoglycemia.10,22 Konjac mannan also
impairs absorption of an intraduoderial sucrose load or of glucose
from an isolated jejunal segment, and it has been suggested that
the gel fibers prevent diffusion of sucrose and glucose from the
gel mass.23
Plasma cholesterol concentrations animals are markedly
influenced by carbohydrates in the diet. Both galactomannans and
glucomannans induce a significant hypocholesterolemic response
when present at low concentrations (0.5% to 3%) in cholesterolsupplemented diets in rats.23 Guar gum (galactomannan) at levels
of 5% to l0% of diet reduced cholesterolemia in chickens fed a
basal casein-sucrose diet containing 1% cholesterol.24 In rats, a
level of
291 © 1989 Butterworth Publishers
Mol. Biother., 1989, vol. 1, No, 6
5% to 19% guar gum was required in the diet to significantly
lower serum and liver cholesterol.24 Konjac mannan can also
induce hypocholesterolemia.25 The active principle appears to be
the mannan itself, since its hydrolysis by cellulase destroyed the
hypocholesterolemic activity.26 The activity of the mannan is
roughly proportional to the molecular weight of its constituent
glucomannans and to its viscosity.10 In adult rats, transport of 14 C
-labeled cholesterol into the plasma and liver was significantly
reduced by Konjac mannan.27 Konjac mannan probably decreases
intestinal absorption of bile salts by interfering with their active
transport mechanism.28 In studies using everted ileal sacs, bile
acid transport was decreased as much as 50% by the presence of
0.25% Konjac mannan in the mucosal medium. The mannan did
not influence the transport of cholic acid, nor did it bind to cholic
acid or taurocholate. It did, however, reduce their active transport
to 30% to 50% of control values. The minimum effective
concentration of Konjac mannan was l0-6 M. Cholesterol uptake
from a micellar solution infused into the proximal jejunum in rats
was significantly retarded by adding as little as 0.1% Konjac
mannan to the micellar solution. The hypocholesterolemic effect
of Konjac mannan, therefore, appears to be due to inhibition of
cholesterol absorption in the jejunum and of bile salt absorption in
the ileum. The effect is reversible when the mannan is removed.
Effects of Mannans on the Immune System
The most marked biological activities of mannans in mammals are
activation of macrophages and stimulation of T cells. As a result,
they are potent immunostimulants with significant activity against
infectious diseases and tumors. It is predicted that this is where
their major influence on human health will lie.
Mannose/mannan receptors and binding proteins
Macrophages possess protein receptors specific for d- mannose.
These receptors are found not only on the surface of the cells but
also intracellularly.29 The function of these receptors is to promote
pinocytosis and ingestion of mannose-terminated glycoproteins.30
It is probably for this reason that mannosylated liposomes are
superior to nonmannosylated liposomes in their immunoadjuvant
properties.31 In addition, certain bacteria interact, via mannoseterminating ligands on their surface, with mannose receptors on
phagocytes and stimulate a process called lectinophagocytosis.
32
Free mannans can therefore inhibit binding and phagocytosis of
yeast particles (zymozan) by mouse peritoneal macrophages,
although there are variations in the ability of’ mannans from
different sources to do this.33 It is suggested that this is a
competitive effect in which free mannan blocks mannose
receptors. The most effective inhibitor of yeast phagocytosis is a
mannan from a mutant of S cerevisiae. Cell wall mannans with
β- (1, 6) linkages and yeast extracellular mannans are much less
effective in blocking phagocytosis.34 Once the mannose receptormannan complex is internalized, the ligands are degraded and the
receptor recycles back to the cell surface.35 Mannose-binding
proteins are also found on hepatocytes and in the spleen, lung, and
lymph nodes, and appear to be similar to those on macrophages. 36
A mannose-b protein of 500 kd is found in rabbit serum, whereas
the human serum mannose-binding protein is 600 kd.36 It is
believed that the function of these proteins is to bind microbial
mannans, promoting phagocytosis. Mannose-modified proteins
are rapidly ingested by macrophages, while the specific delivery
of muramyl dipeptide chemically coupled to mannose-bovine
serum albumin (BSA) significantly activates macrophages. 37
Lymphocytes may also possess a mannose or mannan receptor
because the phosphomannan-ester core structure from Hansenula
holstii blocks the binding of lymphocytes to both rat and mouse
peripheral lymph node high endothelial venules.38
Macrophage activation
Saccharomyces mannan (150 mg/kg/d) enhances car bon
clearance in normal male ddl mice, presumably acting as a
reticuloendothelial system stimulant.39 This same mannan also
increases the number of anti body-forming cells in the spleen.40 In
vitro studies with mouse peritoneal cells (a mixture of
macrophages and lymphocytes) indicate that some mannans and
mannan-protein complexes can stimulate interferon release both
in vivo and in vitro.41 The mannans stimulated interferon release
in a manner similar to endo-toxins, but in contrast to endotoxins,
caused minimal toxicity.42,43 The mannan from C albicans is
active in this way, but the mannan from S cerevisiae is inactive
and inconsistent or poor results have been obtained in other
laboratories.44 These differences may be due to slight structural or
size differences in the polymers.45 The latter is more likely since
low (Mr) mannans tend to be most active (5.5 to 20 kd) in the
interferon-inducing assay, and mannan from Saccharomyces
organisms tends to be larger than mannan from Candida
organisms.
A galactomannan of 20 kd from Lipomyces starkeyi had weak
interferon-inducing properties. In contrast, C albicans mannan
induced the appearance of interferon activity 2 to 24 hours after
intravenous administration.42
DMG, a degraded mannoglucan from Microellobosporia grisea
culture fluid, can stimulate cytotoxic activities of macrophages,
natural killer cells, and killer T cells, and it enhances the activities
of interleukin-l and colony-stimulating factors. It has more potent
antitumor activity than lentinan (a glucan from Lentinus
edodes).13,46-7 DMG stimulates macrophages to pro duce increased
amounts of interleukin-l; In addition, DMG enhances antibody
production against sheep erythrocytes, natural killer activity of the
respiratory burst and selectively inhibited extracellular
accumulation of myeloperoxidase after a phagocytic stimulus. It
has been suggested that the mannan can bind to the neutrophil
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1989 Butterworth Publishers
Mol. Biother., 1989, vol. 1, No, 6
spleen and peritoneal cells, and cytostatic activity of penitoneal
macrophages.46
Monocytes exposed to acemannan and then cultured with T
lymphocytes permitted the T cells to respond in an enhanced
fashion to Phytohemagglutinin this result suggests that the
mannan Stimulated release of helper factors from monocytes.
Acemannan alone is not directly mitogenic for T cells. 8
Antiviral effects
Mannose-binding proteins have been identified ii the serum of
rabbits and in the liver and serum of humans and laboratory
rodents. These proteins can bind glucomannans, such as those
found in cell walls of bacteria, yeasts, and fungi and in envelope
glycoproteins of certain viruses, such as the human
immunodeficiency virus (HIV). In humans, the major mannosebinding protein is an acute-phase protein; its levels increase in
stressed individuals.48 The envelope glycoproteins of HIV (gp 120
and gp 41) contain mannose-rich oligosaccharides that appear to
be potential ligands for the mannose-binding protein. As a result,
the mannose binding protein can inhibit HIV infections of
lymphoblasts and bind selectively to H1V-infected cells. Free
yeast mannan can competitively interfere with binding of this
protein to infected cells. Thus, factors that induce an increase in
the level of the mannose-binding protein may confer protection
against HIV.
Immunosuppression
Both cell- and neutrophil-mediated fungicidal activities may be
depressed in patients with candidiasis.49 Binding of myeloperoxidase to target yeasts is required for the killing of C
albicans.50 The addition of soluble mannan significantly reduced
myclopcroxidase-mediated killing in a dose-dependent manner by
antagonizing binding of myeloperoxidase to the yeasts. Soluble
mannan was demonstrated to have a similar dose-dependent
inhibitory effect on neutrophil-mediated candidacidal activity
without influencing phagocytosis of the organism. A factor
derived from the serum of patients with chronic mucocutaneous
candidiasis inhibits cell-mediated immune function (lymphocyte
proliferation) and has been characterized as a soluble mannan
from the yeast cell walls.51 Saccharomyces mannan has been
tested for its effect on human neutrophil functions.52 The mannan
reduced myeloperoxidase because they cosediment on
centrifugation.49 The mannan facilitates the attachment of the
enzyme to the surface of target yeasts to increase fungicidal
activity of the enzyme.53 The soluble mannan is inhibitory for
both extracellular and intracellular killing of Candida yeasts.50
Mannan concentrations of over 100 ụg /ml have been measured in
the serum of patients with systemic candidiasis. Detection of this
can be used for diagnostic purposes.54
Inhibition of neutrophil binding to C albicans was specifically
blocked by purified mannans from Candida organisms; this
suggests that neutrophils bind to these fungi by means of a
mannan receptor on their surface.55 Blockage, however, was only
effective at high mannan concentrations. It is more likely that the
natural blockers of neutrophil adhesion in Candida supernatants
are mannoproteins.56 S cerevisiae mannan slightly inhibited
peritoneal macrophage phagocytosis of C albicans yeast cells,
either unopsonized or opsonized by C3. It had no effect when
these same yeasts were opsonized with normal human serum or
immunoglobulins. The mannan had no effect on phagolysosome
fusion.57
Mannan isolated from S cerevisiae can inhibit responses of
lymphocytes in vitro to Phytohemagglutinin and pokeweed
mitogen, as well as to Candida organisms, streptococcus, mumps,
and cytomegalo- and herpes simplex virus.58 This is largely due to
the presence of copper in the mannan and possibly due to the
superoxide dismutase activity of the copper-mannan complex.
The mannan increased hydrogen peroxide production and
decreased superoxide production in dose-dependent manner. It did
the same for neutrophils and macrophages. Thus, H2O2
accumulated in the lymphocyte cultures. Chelating the copper
removed most of the inhibiting activity. The accumulated H 2O2
may have been mildly toxic for the lymphocytes.58
Bone marrow stimulation
Mannan-A is a bone marrow stimulant and can protect mice
against cobalt-60 radiation when given before radiation. If given
after irradiation, mannan-A enhances endogenous colony
formation.59 DMG also increases the level of granulocyte /
macrophage colony-stimulating activity in serum. Mannan-R is
ineffective in this regard.59
Wound Healing
Healing of burns was enhanced in guinea pigs treated with aloe
vera extract.60 It is believed that the active fraction of this extract
is acemannan. Guinea pigs received full-thickness burns covering
3% of their body surface. The dressings on these burns were
changed daily and the wounds were examined. The average time
to complete healing in the control group was 50 days. The only
significant difference was found in the aloe vera treated animals,
which healed in an average of 30 days. Wound bacterial counts
were also significantly depressed by the aloe vera extract. 60 In
contrast to these results, Kaufman et al.61 found that an aloe vera
extract hindered healing of experimental second-degree burns in
guinea pigs. However, a review of the techniques used to produce
the aloe vera extract for Kaufman et al. ‘s experiments suggests
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Mol. Biother., 1989, vol. 1, No, 6
that ace-mannan was removed or destroyed since no attempt was
made to stabilize the product by destroying mannanases. The
extract was also treated with activated charcoal, a process that
removes acemannan.
Effects of Mannans on Tumors
Although common polysaccharides such as starch (an ἀ- (1,4)
glucan), dextran (an ἀ-(l,6) glucan), and insulin (a fructan), do not
have antitumor activity,62 there is abundant evidence that mannans
and selected glucans are potent anti-cancer agents.63 The factors
that determine whether a polysaccharide will have antitumor
activity are unclear. However, there appears to be a direct
relationship between the antitumor activity of polysaccharides and
their ability to interact with serum albumin.64 This may simply
reflect the ability of these molecules to bind to proteins. The
soluble D- glucans have antitumor activity if they are mainly
linear, without excessively long branches, and are relatively
resistant to degradation by glucanases.64 Thus, glycogen, starch,
and dextrans are inactive. Compounds with long stretches of β-(l,
3) linkages are effective.64 Loss of tertiary structure by
denaturation also causes loss of activity. Dextrans may be
activated if attached to diethylaminoethyl groups. Studies on
synthetic β-(l , 6)- linked celluloses suggest that antitumor activity
against sarcoma- l80 is greatest in molecules with a high degree of
polymerization and a homogeneous distribution of side chains. 65
One of the earliest records of polysaccharide anti-tumor activity
was recorded in 1947 by Diller,66 who showed that Serratia
marcescens polysaccharide induced destructive changes in
transplantable mouse sarcoma-37. Other early studies67 indicated
that when injected intraperitoneally, a polysaccharide from
Candida guillermondi resulted in regression of sarcoma-37 in
67% of treated animals versus 6% of controls. Histological
examination revealed severe necrosis of the tumor. It has been
suggested that the effect of these bacterial polysaccharides is due
to a reduction in tumor blood flow as a result of hypotension. 68
Mannans with significant antitumor activity have been isolated
from several species of yeast and have been tested for activity
against sarcoma-180.69 (Sarcoma- 180 is an experimental mouse
tumor that is remarkably susceptible to immunological attack. As
a result, it is used as a screening system for immunologically
mediated antitumor activity.70 It is also of interest that immunity
to sarcoma-180 can be transferred by peritoneal exudate cells but
not by spleen cells, lymph node cells, or serum, 71suggesting that
the immunity is due to enhanced macrophage activity).
Effects
Mannan fractions from five species of yeast, C albicans B-792, C
albicans A-207, C stellatoidea, C utilis, and S cerevisiae, were
tested for activity against sarcoma-180 in Swiss albino mice.69
The inhibiting activity at the end of 5 weeks was 99%, 65%, 82%,
10% mannan. The peak blood level was reached 3 hours after
intraperitoneal inoculation.
mannan accumulated in the sarcoma as well as in the liver and
spleen of injected mice.74 The tumor took up about 10% of the
and 91%, respectively. There appeared to be no relationship
between the amount of glucose in these mannans and their
activity, although this is disputed: However, the mannan from C
utilis, which contained an ἀ-linked glucose, was poorly
inhibitory, whereas the fraction from C albicans B-792, which has
a β-g1ucan component, was highly active. It was suggested that
the antitumor activity depends on the presence of the β-linkages.
Mannans from S cerevisiae” and C utilis inhibit the growth not
only of sarcoma-18073,74 but also of 3-methylcholanthrene-induced tumors,75,76 Ehrlich carcinoma, and NF sarcoma. None of
these mannans are active against the ascites form of sarcoma180.72 The mannoglucan from M grisea has antitumor activity
against the MH 134 hepatoma in C3H/He mice.77
Inhibition of the development of 3-methylcholanthrene - induced
tumors occurred in mice pretreated daily with S cerevisiae
mannan,76 3-Methyicholcholanthrene in benzene was applied to
the skin of 4-week-old ddl strain mice. Before application of 3methylcholanthrene, the mice received ten daily injections of S
cerevisiae mannan (100 mg/kg/d intraperitoneally). After
exposure, they received the same do three times a week. Ten
malignant tumors developed in the 20 control mice, whereas only
two tumors de- veloped in the mannan-treated animals. The
average diameter of the tumors in the control animals was 8.6
mm; in the treated animals, it was 2.0 mm.
A hot-water extract of C utilis composed mainly of mannan had a
significant inhibitory effect on subcutaneously transplanted
sarcoma-180 in mice when it was given as ten daily
intraperitoneal injections (100 mg/kg/d) started 24 hours after
tumor inoculation.3 This same extract also slightly inhibited
Ehrlich carcinoma and NF sarcoma. It had no effect on growth of
the ascites form of the tumor or of Yoshida sarcoma. In spite of
minor structural differences between the mannans of C utilis and
S cerevisiae, they show similar spectra of antitumor activity.
Polymerization appears to be essential for the antitumor activity
of these mannans because hydrolysis to small polymers (one sixth
of the original size) results in loss of activity. 76 In addition, it has
been suggested that these antitumor mannoglucans share a unique
tetrasaccharide repeating-unit structure and (Mr) of approximately
3 to 10 x 102 kd.46
The carboxymethyl derivative of this Candida organism mannan
was also tested in the sarcoma-180 system. The derivative was
administered by several different routes, the most effective of
which were intraperitoneal and intravenous. Much less effective
was subcutaneous and oral administration. Antitumor efficacy
was similar to the unmodified mannan, and the most effective size
was 20 to 30 kd78.Tritium-labeled carboxymethyl Candida sp.
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MG, the mannoglucan from M grisea, lentinan (a branched glucan
from Lentinus edodes), bacterial lipopolysaccharide, and TAK (a
linear glucan from Alcaligenes faecalis) were tested for antitumor
activity by inoculation directly into the MH 134 hepatoma in
C3H/He mice. 77All but TAK had similar antitumor activity when
administered intraperitoneally but different activities when
administered directly into the tumor. MG and lentinan had the
most potent activity intratumorally. These compounds caused
almost complete regression of the tumor, whereas TAK had no
detectable antitumor activity. MG has potent antitumor activity
against the Ehrlich carcinoma and against MM46 syngeneic
adenocarcinoma, with high rates of complete regression. 47
Mode of action
When mannoglucan prepared from M grisea was administered
intravenously to C3H mice bearing the solid MH 134 hepatoma,
the blood circulation in the tumor was inhibited within 6 hours
and tumor growth was retarded within 3 days. The tumor mass
was excised and extracted at various intervals after administration
of mannan. A cytotoxic factor was produced that was detectable
in the tumor homogenate by an 8-hour cytolysis assay against L929 fibroblasts. With out mannoglucan treatment, the cytotoxic
activity was absent. The molecular size of the factor was 70 to 80
kd, and it is probably a type of tumor necrosis factor since the
cytotoxic factor was inhibited by anti- tumor necrosis factor
(TNF) serum. The dose dependencies of the cytotoxin and TNF
were similar.77
Yeast mannan can induce a stronger antitumor response in the
sarcoma- 180 system of mice than the glucan from the same
source.3 Lymphocytes isolated from the regional lymph nodes of
mice that were previously injected with glucan or mannan can
inhibit growth of sarcoma-l80 cells in vivo.40
The antitumor activity of mannans is probably a direct result of
their macrophage -stimulating activity. Thus, ingestion of large
mannan molecules causes secretion of interleukin-l, interferon,
and TNF. Their lack of significant toxicity, in combination with
this stimulating activity, makes mannans prime candidates for
further investigation as antitumor agents.
References
I. Davis SE. Lewis BA, Physiological effects of mannans
galactomannans and glucomannans. In: Jeanes A, Hodge J, eds.
American Chemical Society Symposium Series 15, Washington,
DC American Chemical Society. 1975.
2. McMurrough I, Rose AH, Effect of growth rate and substrate
limitation on the composition and structure of the cell will of
Saccharomyces cerevisiae. Biochem / 1967; 105:189-203
3. Oka S., Kumano N., Sato K. et al. Antitumor activity of some
plant polysaccharides II. Chemical constituents and antitumor
activity of yeast polysaccharide, Gann 1969; 60:287-93.
4. Oka S., Okamura N, Kits S. et al., Antitumor activity of some
plant polysaccharides. I. Fractionation and antitumor activity of
basasse polysaccharide. Gann, 1968; 58:35-42
21. Reffo CC, Ghirardi FE, Forattini C. Glucomannan in
hypertensive patients: Pilot clinical trial. Curr Therapeutic Res
1988; 44:22-7.
5. Bishop CT, Blank F, Gardner PE. The cell wall polysaccharides
of Candida albicans: Glucan, mannan, and chitin. Can J Chem
1960; JL8
295 ©
6. Saxena A., Hammer CF., Cihlar RL. Analysis of mannans of
two relatively avirulent mutant strains of Candida albicans.
Infect Immun 1989; 57:413-9.
7. Wheat RW, Woodruff WW. , Haltiwanger RS. Occurrence of
antigenic (species-specific?) partially 3-O-mcthylatcd
heteromannans in cell wall and soluble cellular (non-wall)
components of Coccidioides immitis mycelia. Infect Immun 1983;
41:728-34.
8. Womble D., Helderman JH., Enhancement of alloresponsiveness of human lymphocytes by acemannan
(Carrisyn®). Int. J Immunopharmacol.1988; 10:967-74.
9. Ramsdcn L., Northcote DH. Glucomannan synthesize from
suspension cultures, of Pinus sylvestris. Phytochemistry 1987;
26:2679-83.
10. Ebihara K, Masuhara R, Kiriyama S. Effect of konjac mannan,
a water soluble dietary fiber on plasma glucose and insulin
responses of young men undergone glucose tolerance test. Nutr
Rep Int. 1981, 23:577-83.
11. Kato K, Matsuda K. Studies on the chemical structure of
konjac mannan. Part I. Isolation and characterization of
oligosaccharides from the partial acid hydrolyzate of the mannan.
Agr Biol Chem 1969; 33:1446-53.
12. Kato K, Watanabe T, Matsuda K. Studies, on the chemical
structure of konjac mannan, Part II. Isolation and characterization
of oligosaccharides from enzymatic of the mannans. Agr Biol
Chem 1970: 34; 532-9.
13. Inoue K. Kawamoto KK, Kadoya S. Structural studies on an
antitumor polysaccharide from Microellosporia grisea.
Carbohydrate Res 1983: 114:245-56.
14. Nakajima H. Kita Y. Takashi T et al. Immunopotentiation by
a new antitumor polysaccharide. DMG, a degraded D-manno-D
glucan from Microellobosporia grisea culture fluid. Gann 1984;
75: 260-8.
15. Emi S. Fukomoto J. Yamamoto T. Crystallization and some
properties of mannanase. Agr Biol Chem 1972: 36:991-1001.
16. Snaith SM. Levvy GA. α-D-Mannosidase. Adv Carbohydrate
Chem Biochem 1973; 28:401-45.
17. Herman RH. Mannose metabolism 1. Am J Clin Nutr 1971;
24: 488-98.
18. McMaster W, Desbaillets L, Menguy R. Glycosidases in
canine pancreatic secretion. Proc Soc Exp Biol Med 1970:
135:87-90.
19. Jones GH, Ballou CE. Isolation of a α- mannosidases which
by hydrolyses yeast mannan. J Biol Chem 1968; 243:2442-46.
20. Eriksson K-E Winell M. Purification a characterization of a
fungal β-mannase. Acta Chem Scand 1968: 22:1924-34.
1989 Butterworth Publishers
Mol. Biother., 1989, vol. 1, no.6
22. Ebihara K. Masuhara R, Kiriyama S. Major determinants of
plasma glucose-flattering activity of a water-soluble dietary fiber:
Effects of konjac mannan on gastric emptying and intraluminal
glucose diffusion. Nutr Rep Int 1981; 23:1145-56.
23. Hopman WPM. Houben PGMP. Speth PAJ, Lamers CBHW,
Glucomannan prevents postprandial hypoglycemia in patients
with gastric surgery. Gut 1988; 29:930-4.
24. Riccardi BA. Fahrenbach MJ. Effect of guar gum and pectin
N.F. on serum and liver lipids of cholesterol fed rats. Proc Soc
Esp. Biol Med 1967: 124:749—52.
25. Kiriyama S, Morisaki H, Yoshida A. Changes in
hypocholesterolemic activity in rats by various Konnyaku powder
treatments. Agr Biol Chem; 1970; 34:641-3.
26. Kiriyama S. Ichihara Y. Enishi A. Yoshida A. Effect of
purification and cellulase treatment on the hypocholesterolemic
activity of crude konjac mannan. J Nutr 1972; 102:1689-98.
27. Kodama. T. Nakai H, Kiriyama S. Yoshidi A.
Hypocholesterolemic mechanisms of non-nutritive
polysaccharides (konjac mannan, pectin, and carboxymethyl) in
foods. J Jpn. Soc Food Nutr 1972; 25:603-8.
28. Kiriyama S. Enishi A. Yura K. Inhibitory effects of konjac
mannan on bile acid transport in the everted sacs of rat ileum. J
Nutr 1974; 104:69-78.
29. Lee YC. Mannose binding proteins of animal origin. Adv Esp.
Med Biol 228:103-21.
30. Stahl P. Gordon S. Expression of a mannosyl-fucosyl receptor
for endocytosis on cultured primary macrophages and their
hybrids. J Cell Biol 1982; 93:49-56.
31. Garcon N. Gregoriadis G. Taylor M. Summerfield J. Mannose
mediated targeted immunoadjuvant action of liposomes.
Immunology 1988; 64:743-5.
32. Ofek I. Sharon N. Lectinophagocytosis: A molecular
mechanism of recognition between cell surface sugars and lectins
in the phagocytosis of bacteria. Infect Immunol 1988; 56:539-47.
33. Sung SJ, Nelson RS, Silverstein SC. Yeast mannan inhibit
binding and phagocytosis of zymosan by mouse peritoneal
macrophages. J Cell Biol 1983; 96:160-6.
34. Sung S-SJ. Nelson RS, Silverstein SC. Mice peritoneal
macrophages plated on mannan - and horseradish pcroxidase
coated substrates lose the ability to phagocytosis by their Fc
receptors. J Immuno 1983: 134; 3712-17.
35. Tietze C, Schlesinger PH, Stahl P. Mannose-specific
endocytosis receptor of alveolar macrophages: Demonstration of
two functionally di intracellular pools of receptor and their roles
in receptor cycling. J Cell Biol 1982: 92:417-24.
36, Kawasaki N. Kawasaki T. Yamashina, I. Isolation and
characterization of mannans-Binding protein from human serum.
J Biochem (Tokyo) 1983; 94:937-47.
49. Wright CD. Bowie JU. Gray CR, Nelson RD. Candidacidal
activity of myeloperoxidase: Mechanism of inhibitory influence of
soluble cell wall mannan. Infect Immun 1983; 42:76-80.
50. Lehrer RI, Kline MJ. Leukocyte myeloperoxidase deficiency
and disseminated candidiasis: The role of myeloperoxidase in
resistance to Candida infection. J Clin Invest 1969; 48:1478-88.
296 ©
1989 Butterworth Publishers
Mol. Biother., 1989, vol. 1, No, 6
37. Roche AC. Midoux P, Mayer R, Monsigny M. Activation of
murine macrophages and human monocytes by membrane lectinmediated endocytosis of activators, bound to neoglycoproteins.
Proceedings of the Eighth International Symposium on
Glycoconjugates, Houston, TX. New York. Praeger, 1985, p.
569.
38. Yednock TA, Stoolman LM. Rosen SD. Phosphomannosyl
derivatized beads detect a receptor involved in lymphocyte
homing. J Cell Biol 1987; 104:713-23.
39. Suzuki M, Chaki F. Suzuki S. Effect of yeast polysaccharides
treatments on the carbon-clearance activity of mice implanted
with sarcoma-180 solid tumor. Gann 1971; 62:553-6.
40. Suzuki S. Suzuki M, Matsumoto T, Okawa Y. Growth
inhibition of sarcoma- 180 solid tumor by the cells of regional
lymph node and spleen of mice administered with yeast
polysaccharides. Gann 1971; 62:343-52.
41. Lackovic V. Borecky L. Sikl D. Master L. Bauer S.
Stimulation of interferon production by mannans. Proc Soc Esp.
Biol Med 1970; 134: 874-9.
42. Borecky L. Lackovic V. Blaskovic D. Masler L. Sikl D. An
interferon-like substance induced by mannans. Acta Virol 1967;
11:264-6.
43. Hasenclever HF, Mitchell WO. Immunological studies on
polysaccharides of yeasts. J Immun 1964; 93:763-71.
44. DeClercq E, Eckstein F. Merigan TC. Structural requirements
for synthetic polyanions to act as interferon inducers. Ann NY
Acad Sci 1970; 173:444-61.
45. Suzuki S. Sunayama H. Saito T. Studies on the antigenic
activity of yeasts. 1. Analysis of the determinant groups of the
mannans of Saccharomyces cerevisiae. Jpn J Microbial 1968;
12:19-24.
46. Nakajima H, Hashimoto S. Nagao S. et al. Host-mediated anti
tumor effect of DMG, a degraded D-manno-D-glucan from
Micraellobasporia grisea culture fluid. Gann 1984; 75:253-9.
47. Inoue K. Nakajima H. Kohno M. et al. An antitumor
polysaccharide produced by Microellobosporia grisea:
Preparation general characterization, and antitumor activity.
Carbohyd. Res 1983; 114:164-8.
48. Ezekowitz RA. Kuhlman M. Groopman JE. Byrn RA. A
human serum mannose-binding protein inhibits in vitro infection
by the human immunodeficiency virus. J. Exp Med 1989;
169:185-96.
51. Fischer A. Ballet J. Griscoll C. Specific inhibition of in vitro
Candida induced lymphocyte proliferation by polysaccharide
antigens present in the serum of patients with chronic
mucocutaneous candidiasis. J Clin Invest 1978; 62:1005-13.
52. Wright CD. Herron MJ. Gray GR. Holmes B. Nelson RD. Influence of yeast mannan on human neutrophil functions:
Inhibition Lion of release of myeloperoxidase related to
carbohydrate binding property of enzyme. Infect Immun 1981;
32:731-8.
53. Lehrer RI. Antifungal effects of peroxidase systems. J
Bacterial 1969; 99:361-5.
54. Weiner MH, Youni WJ. Mannan antigenemia in the diagnosis
of invasive Candida infections. J Clin Invest 1976; 58:1045-53.
55. Diamond RD. Krzesicki R. Mechanisms of attachment of
neutrophils to Candida albicans pseudohyphae in the absence of
serum and subsequent damage to pseudohyphae by microbicidal
processes of neutrophils in vitro. J. Clin Invest 1981; 61:360-9.
56. Diamond RD. Oppenheim F. Nakagawa Y. Krezesicki R.
Haudenschild CC. Properties of’ product of Candida albicans
hyphae and pseudohyphae that inhibits contact between the fungi
and human neutrophils in vitro. J. Immunol 1980; 125:2797-2804.
57. Kolotila MP. Rogers AL. Beneke ES. Smith CW. The effects
of soluble Saccharomyces cerevisdiae mannan on the
phagocytosis of Candida albicans by mouse peritoneal
macrophages in vitro. J. MedVei Myco 1987; 25:85-95.
58. Nelson RD. Herron MJ. McCormack RT. Gehrz RC. Two
mechanisms of inhibition of human lymphocyte proliferation by
soluble yeast mannans polysaccharide. Infect Immun 1984;
43:1041-6.
59. Paichen ML. DiLuzio NR. Jacques P. MacVittie TJ. Soluble
polyglycans enhance recovery from cobalt-60 induced
hemopoietic injury. J. Biol Resp. Mod l984; 3:627-33.
60. Rodriguez-Bigas M. Cruz NJ. Suarez A. Comparative
evaluation of aloe vera in the management of burn wounds in
guinea pigs. Plast Reconstir Surg 1988; 81:386-9.
61. Kaufman T. Kalderon N. Ullmann Y. Berger J. Aloe vera gel
hindered wound healing of experimental second-degree burns: A
quantitative controlled study. J. Burn Care Rehabil 1988; 9: 1569.
62. Hamuro J. Chihara G. Effect of antitumor polysaccharides on
the higher structure of serum protein. Nature 1973: 245:40-1.
63. Kamasuka T. Momoki Y. Sakai S. Antitumor activity of
polysaccharide fractions prepared from some strains of
Basidiomycetes. Gann 1968; 59:443-5.
64. Whistler RL. Bushway AA. Singh PB. Nakahara W. Tokuzen
R. Noncytotoxic, antitumor polysaccharides. Adv. Carbohydr
Chem Biochem 1976; 32:235-75.
72. Oka S. Kumano N, Sato K. et al. Antitumor activity of some
plant polysaccharide. II. Chemical constituents and antitumor
activity of yeast polysaccharide. Gann 1969; 60:287-93.
73. Kumano N. Kurita K. Oka S. Distribution of
carboxymethylated yeast mannan in normal and tumor bearing
mice. Gann 1972; 63:675-83.
65. Matsuzaki K, Yamamoto I. Sato T. Synthesis of water-soluble
branched polysaccharide, and their antitumor activity. 1.
Branched polysaccharides from cellulose acetate. Makromol
Chem 1985; 186:449-36.
66. Diller IC. Degenerative changes induced in tumors by S.
marcescens polysaccharide. Cancer Res. 1947; 7:605-26.
67. Zankowski ZT. Yamashita M. Diller IC. The effect of
Candida guillermandi polysaccharide on transplantable mouse
sarcoma 37. Proc Soc Esp. Biol Med 1957: 96:79-80.
68. Algire GH. Legallais FY. Anderson BF. Vascular reactions of
normal and malignant tissues in vivo. V. The role of hypotension
in the action of a bacterial polysaccharide on tumors. JNCI 1952;
12:1279-91.
69. Suzuki S. Hatsukaiwa H. Sunayama H. et al. Antitumor
activity of polysaccharides. II. Growth - activity of mannan
fractions isolated from several species of yeast against sarcoma
180 solid tumors. Gann 1969; 60:65-9.
70. Bradner WT, Clarke DA. Stimulation of host defense against
experimental cancer. II. Temporal and reversal studies of the
zymosan effect. Cancer Res 1959; 19:673-8.
74. Abe S. Takasashi K. Tsubouchi J. Aida K. Yamazaki M.
Mizuno D. Different local therapeutic effects of various
polysaccharides on MHl34 hepatoma in mice and its relation to
inflammation induced by the polysaccharides. Gann 1984:
75:459-65.
75. Kumano N. Kurtia K. Oka S. Inhibition of the development
of3-methylcholanthrene-induced mouse tumor with the yeast
mannan preparation. Gann 1973; 64:529-33.
76. Oka S. Kumano N. Kurita K. Antitumor activity of the yeast
mannan preparation in relation to the effect of chemical
modification. Gann 1972; 63:365-9.
77. Takahashi K. Watanuki Y. Yamazaki M, Abe S. Local
induction of a cytotoxic factor in murine tumour by a systemic
administration of an antitumor polysaccharide. Br. J. Cancer
1988; 57:170-3.
78. Suzuki S. Suzuki M. Hatsukaiwa H. et al. Antitumor activity
of polysaccharides. III. Growth-inhibitor activity of purified
mannan and glucan fractions from baker’s yeast against sarcoma180 solid tumor. Gann 1969; 60:273-7.
71. Macda Y. Chihara G. Periodical consideration on the
establishment of antitumor action in host and activation of
peritoneal exudate cells by lentinan. Gann 1973; 64.351-7.
296 ©
1989 Butterworth Publishers
Mol. Biother., 1989, vol. 1, No, 6