The Use of Mushroom Glucans and Proteoglycans in Cancer Treatment

Page 4 Alternative Medicine Review ◆ Volume 5 Number 1 ◆ 2000

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

The Use of Mushroom Glucans andProteoglycans in Cancer Treatment

by Parris M. Kidd, PhD

Parris Kidd, PhD (Cell biology, University of California at Berkeley); Contributing Editor, Alternative Medicine Review; Healtheducator and biomedical consultant to the supplement industry.Correspondence address: 535 Pierce St. Suite 209 Albany, CA 94706.

AbstractImmunoceuticals can be considered as substances having immunotherapeutic efficacywhen taken orally. More than 50 mushroom species have yielded potentialimmunoceuticals that exhibit anticancer activity in vitro or in animal models and ofthese, six have been investigated in human cancers. All are non-toxic and very welltolerated. Lentinan and schizophyllan have little oral activity. Active Hexose CorrelatedCompound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway.Two proteoglycans from Coriolus versicolor – PSK (Polysaccharide-K) and PSP(Polysaccharide-Peptide) – have demonstrated the most promise. In Japanese trialssince 1970, PSK significantly extended survival at five years or beyond in cancers ofthe stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types),and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II andPhase III trials in China. In double-blind trials, PSP significantly extended five-yearsurvival in esophageal cancer. PSP significantly improved quality of life, providedsubstantial pain relief, and enhanced immune status in 70-97 percent of patients withcancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boostedimmune cell production, ameliorated chemotherapy symptoms, and enhanced tumorinfiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, provenbenefits to survival and quality of life, and compatibility with chemotherapy and radiationtherapy makes them well suited for cancer management regimens.(Altern Med Rev 2000;5(1):4-27)

IntroductionAs the new millennium dawns, humanity continues to strive for longer lifespan and

better quality of life. But the disease of cancer continues to be the scourge of humanity; being aleading cause of early death, and resistant to therapies aimed at its eradication. Now anotherdimension of anticancer therapy is available – immunotherapy, a means by which the body’simmune defenses, beaten down by the cancer and by toxic therapies used against the cancer,can be revitalized to carry out their natural functions of eliminating abnormal tissues from thebody. The tools for immunotherapy are naturally-occurring substances, herein christenedimmunoceuticals, which can be included in the general category of nutraceuticals, or dietarysupplements.


Mushroom

Glucans &

Proteoglycans

Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 5

Mushrooms havebeen recognized for theirmedicinal properties for fivemillennia.1 It was not untilthe last one-third of the pastcentury that technology wascapable of biochemicallydissecting traditional medici-nal mushrooms and isolatingtheir most active anticancerconstituents. Once concen-trates of such substances be-came reliably available, theywere screened in animalmodels of cancer prior to ap-propriate anticancer applica-tion in humans. Some ofthese mushroom-derivedsubstances were found to behighly potent immune sys-tem enhancers, potentiatinghuman immunity againstcancer more effectively thanother anticancer agents. Thisreview focuses on mushroomimmunoceuticals; prepara-tions from mushroomswhich have been systemati-cally investigated for theiroral anticancer action.

Mushroom Immunoceuticals – AnOverview

Immunoceuticals isolated from morethan 30 mushroom species have shownanticancer action in animals.2 Only a handfulhave been taken to the next step: objectiveclinical assessment for anticancer potential inhumans. Of these relative few, all arechemically ß-D-glucan in nature (i.e., linearpolymers of d-glucose with othermonosaccharides) or ß-D-glucans linked toproteins (so-called polysaccharide-peptides,more formally termed “proteoglycans”– seeFigure 1). As a rule, the protein-linked glucans

have greater immuno-potentiation activity than thecorresponding free glucans.3

The basic ß-D-glucan is a repeating struc-ture, with its D-glucose mol-ecules joined together in lin-ear chains by beta-bonds (ß).These can extend from thecarbon 1 of one saccharidering to the carbon 3 of thenext (ß1-3), from carbon 1to carbon 4 (ß1-4), or fromcarbon 1 to carbon 6 (ß1-6).Most often there is a mainchain which is either ß1-3,ß1-4, or mixed ß1-3, ß1-4with ß1-6 side chains. Thebasic repeating structure ofa ß1-3 glucan with ß1-6 sidechains is shown in Figures2a and 2b. Hetero-ß-D-glucans, i.e., linear polymersof glucose with other D-monosaccharides, can haveanticancer activity, but al-pha-D-glucans from mush-rooms usually lack antican-cer activity.6

Six mushroompreparations have shown

clinically significant efficacy against humancancers: lentinan, schizophyllan, Active Hex-ose Correlated Compound (AHCC), MaitakeD-Fraction, Polysaccharide-K, and Polysac-charide-P. Since lentinan and schizophyllanhave limited oral bioavailability, and thereforefail to meet the definition of immunoceutical,they will only be given a cursory review.AHCC and Maitake D-Fraction are still in theearly stages of investigation. The remainingtwo have been subjected to in-depth applica-tion against cancers in humans.

Glucan Chains

Core Proteinsor Polypeptides

Figure 1. The molecular plan ofa mushroom proteoglycan. Thecentral, linear polypeptide chainhas multiple, branched chains ofpoly-beta-D-glucans attached.Modified from Molecular Biology of the Cell.7

Page 6 Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000


Lentinan from ShiitakeLentinan, produced from the Shiitake

mushroom Lentinus edodes, is a ß1-3, ß1-6 D-glucan. Glucan preparations are always het-erogeneous in molecular weight, but lentinanis particularly large, on the order of 400,000-1,000,000 daltons. Its oral bioavailability isreportedly limited; thus, it has been routinelyadministered intravenously. Open-label clini-cal studies indicate lentinan can prolong lifein patients with gastric or colorectal cancer,as reviewed recently by Borchers et al.1

Lentinan has been satisfactorily proven to po-tentiate human immunity.1,2,8

Schizophyllan (SPG, Sonifilan,Sizofiran, Sizofilan)

Schizophyllan, from Schizophyllumcommune, is another ß1-3, ß1-6 D-glucan toolarge for effective oral administration. Its mo-lecular weight ranges around 450,000 daltonsand it is usually administered by intramuscu-lar injection. Schizophyllan was found ratherineffective against gastric cancer, but extendedsurvival time in patients with head and neckcancer.1,9 In cervical cancer, schizophyllan pro-longed survival and time to recurrence forstage II cases but not stage III,10-12 and showedadded effectiveness when injected directly intothe tumor mass.13

Active Hexose CorrelatedCompound (AHCC)

Active Hexose Corre-lated Compound (AHCC) is aproprietary extract prepared fromco-cultured mycelia of severalspecies of Basidiomycete mush-rooms, including shiitake(Lentinus edodes). Mushroomsources and details of the meth-ods of preparation have not beenfully disclosed.14 The extract ismade using hot water following

an enzyme pretreatment; it contains polysac-charides, amino acids, and minerals, and isorally bioavailable. According to its manufac-turers, the glucans in AHCC have low molecu-lar weight (around 5,000 daltons) and are ofthe alpha-1,3 type.14 Both these attributes arepeculiar for immunoactive mushroom glucans– typically such low-molecular weight mate-rial is inactive, and as a rule the alpha-glucanshave minimal immuno-potentiating activity;

HO

CH2OHO

OH

6

123

β

CH2OHO

OH

1

HO

CH2

O

OH

6

123

βO

HO

CH2OHO

OH

6

123

βOO

β

Oβ

HO

OH

n

Figure 2a. Primary molecular diagram of mushroom beta-D-glucans. From Yanaki et al4

6

6

6

6

6

6

3

3

3

2

2

22

2

1

1

1

ββ

2

Figure 2b. Higher-level molecular diagram of mushroom

beta-D-glucans. From Bluhm5

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yet animal research and preliminary humanstudies indicate AHCC has anticancer efficacy.

Beginning in 1992, Kamiyamaconducted a trial in Japan to evaluate thepreventive effect of AHCC against recurrenceof hepatocellular carcinoma following surgicalresection.15 After surgery, 126 patients wereseparated into two groups: 44 patients wereadministered AHCC, 3 grams per day orally,while the other 82 served as controls.Unfortunately, the outcome of this trial ispublished to date only in abstract form. Theinvestigators reported that after one year theAHCC group showed a significantly highersurvival rate than the control group, as well assignificant lowering of certain tumor markersin the serum.

In another published abstract based onthis same study, Kamiyama et al stated livertumor recurrence was not lower in the AHCCgroup, although the survival rate was higher.16

They claimed AHCC-treated patients who ex-perienced improved survival were positive forhepatitis C; and patients who were either hepa-titis B-positive or negative for hepatitis virusesdid not experience better survival rates. Theyreported the AHCC-treated patients also hadsignificantly decreased levels of liver damagemarkers SGOT and SGPT. Among these pa-tients, significant improvements were noted inlymphocyte and red cell counts, and in appe-tite and anemia.14 In four cases where cirrho-sis was also present, ascites developed and wassuccessfully treated with 3-6 grams/day ofAHCC.

The AHCC Research Association wasformed in Japan in 1996 to foster the develop-ment of AHCC as an anticancer therapy. Intheir circulating abstracts14 they report on otherpreliminary studies with AHCC against can-cer. They state that of 300 cancer patients ad-ministered AHCC, 58 were effectively treated,with 46 showing complete or partial regres-sion and 12 experiencing no change of tumorsize. Among these 58 cases were cancers of

the lung, breast, stomach, esophagus, colon,liver, and several other sites. It is not possiblefrom the limited data to calculate relative effi-cacies, improvements in survival or recurrence,or quality of life benefit for any of these can-cers. Research on AHCC is at a comparativelyearly stage, but its declared efficacy againstliver cancer warrants further investigation.

Maitake D-FractionMaitake D-Fraction is a mixed ß-D-

glucan fraction prepared from the maitakemushroom (Grifola frondosa) and is orallybioavailable (see Jones17 for an overall review).Maitake has been used as food in Japan forhundreds of years, in amounts up to severalhundred grams per day, and its safety is estab-lished. A hot-water extract from the fruitingbody of the mushroom was found to be highlypotent against human cancer cells in culture.Subsequently, the D-fraction was preparedfrom the crude hot-water fraction bydeproteination.17

Maitake D-Fraction contains mainly ß-D-glucan material with 1-6 main chains and1-4 branchings, and the more common 1-3main chains and 1-6 branchings.18 This frac-tion also is highly active in vitro and in animalmodels of cancer, although activity in theseexperimental systems does not necessarily pre-dict anticancer efficacy in humans.

Maitake D-Fraction has been used ina few exploratory studies in cancer patients.17

In 1994, a group from China published in ab-stract form their findings from a pilot studyon 63 cancer patients. They reported the totaleffective rate against solid tumors at higherthan 95 percent, and the effective rate againstleukemia higher than 90 percent.17 Unfortu-nately, the concentration of the extract usedwas not disclosed.

In 1995, Nanba published an informalsummary of an open-label, non-randomizedstudy conducted in Japan.19 In this study, 165patients with various cancers, many with



advanced progression and some refusingchemotherapy, were treated with D-Fractionplus tablets of dried crude extract of maitake.Dosages varied from patient to patient, withD-fraction doses ranging from 35-100 mg perday and crude mushroom extract ranging from4-6 grams. Symptomatic improvements orregression were claimed for approximately 73percent of the breast cases and 67 percent ofthe lung cases. Of the liver cancer cases, 47percent were said to have responded, whichjumped to 73 percent when chemotherapy wasalso utilized. In contrast to the incredibleresponse rates claimed in the Chinese study,in the Japanese study less than 50 percent ofthe leukemias and cancers of the prostate,brain, stomach, and bone seemed to respond.The disease subgroups were small, however,the largest number of cases studied being 19(liver cancer, with chemotherapy). Accordingto Nanba, 83 percent of the patientsexperienced lessening of pain, and 90 percentexperienced improvement of chemotherapy-related symptoms such as vomiting, nausea,reduced appetite, hair loss, intestinal bleeding,and lowered white cell count.

These claims of benefit from MaitakeD-fraction are encouraging. In the absence ofadequate peer review and especially withoutaccess to the primary data, however, it is diffi-cult to assign meaning to them. Nonetheless,several U.S. physicians have reported goodresults with Maitake D-fraction in their prac-tices, and an Investigative New Drug approvalwas obtained in 1998 to begin a Phase II pilotstudy with this material on patients with ad-vanced breast and prostate cancer.20

Proteoglycans from Coriolusversicolor

The mushroom-derived “polysaccha-ride-peptides,” or proteoglycans, are polypep-tide chains or small proteins to which polysac-charide ß-D-glucan chains are stably attached.Up to this point, PSK and PSP are the only

two proteoglycans systematically investigatedin human cancers.

Coriolus versicolor (formerlyTrametes versicolor, Polyporus versicolor) isa mushroom which grows on tree trunks andbelongs to the more-advanced Basidiomycetesclass of fungi. This mushroom has long beentreasured in the East; in Japan it is known askawaratake (“mushroom by the river bank”),and in China it is called Yun Zhi or “cloud fun-gus.” In Japan around 1965 a chemical engi-neer investigated Coriolus versicolor for itsanticancer constituents after observing hisneighbor’s life-threatening cancer was curedafter taking Yun Zhi. This led to the discoveryof PSK (Polysaccharide-K).21 The closely-re-lated PSP (Polysaccharide-Peptide) was firstisolated in China some time later, around1983.22

PSK ConstituentsPSK is prepared from strain CM-101

of Coriolus versicolor by water extraction andsalting out. It is approximately 62-percentpolysaccharide and 38-percent protein, al-though the content of both can vary. The glucanportion of PSK consists of a ß1-4 main chainand ß1-3 side chains, with ß1-6 side chainsthat bond to a polypeptide moiety through O-or N-glycosidic bonds. The polypeptide por-tion is relatively rich in aspartic, glutamic, andother acidic amino acids. PSK is a set of mol-ecules whose molecular weight ranges from94,000 to 100,000 daltons, and is bioavailableby the oral route.23 Studies with C14-labeledPSK in mice confirmed its full molecular spec-trum is absorbed within 24 hours followingadministration. Conventional toxicologicalassessments indicate PSK is non-toxic: its oralLD50 is low and no abnormalities have beenobserved in subacute and chronic toxicity tests.

PSK Clinical TrialsThe first clinical trial research with

PSK began around 1970. Decades of clinical

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Glucans &

Proteoglycans



experience indicate PSK is very gentle oncancer patients, its only significant side-effectbeing occasional darkening of the fingernails.To date, PSK is most clinically indicated forcancers of the stomach, esophagus,

nasopharynx, colon, rectum, and lung (seeTables 1 and 2). It has also shown promise ina subset of breast cancers.

Stomach Kaibara et al, 197624 66 PSK w/chemo doubled 2-yr Stage IV Surgery w/MMC survival (p<0.05), incl. pts w/ w/inv., metas. +/- PSK w/chemo invasion-metastasis

Stomach Fujimoto et al, 197925 230 PSK w/chemo extended all stages Surgery +/- PSK w/ survival of one subset (p<0.001) chemo but not poor immune responders

Stomach Hattori et al, 197926 110 PSK w/chemo improved 3-yr Stages I-IV Surgery w/MMC survival (poor stat. analysis)

+chemo +/-PSK PSK no deaths stage III 2 yrs

Stomach, Adv. Kodama et al, 198227 450 PSK w/chemo doubledw/inv., metas. Surgery w/MMC 5-yr survival (p<0.01) +/- PSK w/chemo

Stomach Kondo and Torisu, 198528 144 PSK extended disease-free Stage III Surgery/no chemo +/-PSK period (no p-value given); DOUBLE-BLIND enhanced immunity (p<0.05)

Stomach Mitomi, Ogoshi, 198629 168 PSK extended 5-yr survival Stages I-IV Surgery + chemo +/-PSK (p<0.05)

Stomach, Adv. Niimoto et al, 198830 579 PSK extended 5-yr survival w/inv., metas. Surgery w/MMC (p<0.05); pre-op immunity +/-chemo +/-PSK predicted PSK benefit

Stomach, Adv. Maehara et al, 199030 255 PSK w/chemo extended 15- w/inv., metas. Surgery +/- PSK w/chemo yr survival (p<0.035)

Stomach Tsujitani et al, 199234 53 PSK extended 5-yr survival Stage III Surgery + MMC + chemo (p<0.05) +/-PSK

Stomach, I-IV Nakazato et al, 199432 253 PSK extended 5-yr survivalSurgery + chemo +/-PSK (p<0.05), disease-free

period (p<0.04)

MMC=mitomycin-C; chemo=5-fluorouracil (5-FU) or derivative, long-term, sometimes combined with other agents; PSK=Polysaccharide-K, at 3-6g/day for 1 year or longer. See individual references for details.

Cancer type Authors Subjects Outcome

Table 1. PSK: Controlled Trials in Stomach Cancer



PSK and Stomach CancerStomach cancer continues to inflict

major mortality in Japan and has been theobject of more clinical trials with PSK thanany other cancer. Beginning in 1970, Kaibaraand his colleagues at Kyushu University inFukuoka, Japan, began adding PSKimmunotherapy to their existing chemotherapyprotocols.24 Hoping to achieve a clearcut resultafter two years, they chose to study patientswith advanced (Stage IV) cases with invasionand metastasis, since few such patients survivean additional two years. They first performedconventional surgical resection, administeringMitomycin-C (MMC) beginning on the dayof surgery. The patients were then put on along-term chemotherapy regimen of Futraful,a 5-fluorouracil (5-FU) derivative, withperiodic MMC treatments. PSK was added at3 grams per day orally. The overallcombination regimen was named“chemoimmunotherapy.” This group wasretrospectively compared against a patientgroup treated in earlier years with surgery andMMC, but not with the chemoimmunotherapyregimen.

Kaibara’s group found survival wasbetter in the chemoimmuno- group by morethan double (34% vs 11%, p<0.05) after twoyears.24 This finding was later supported by asimilar trial conducted by Fujimoto and asso-ciates at Chiba University.25 In addition,Hattori’s group at Hiroshima University did atrial in which they also monitored immunecompetence using skin DTH (delayed-type-hypersensitivity) reactions and lymphocyteblastogenesis following induction by mito-gens.26 Treatment after surgery with the com-bination of PSK as immunotherapeutic (6grams/day) and 5-FU as chemotherapeutic wasagain found more effective for long-term sur-vival of stomach cancer patients compared totreatment with MMC only after surgery. In thistrial, the combination of PSK with 5-FU verylikely increased three-year survival. Although

the statistical analysis was flawed, survivaldata clearly indicated benefit after the firstyear, and among Stage III patients taking thecombination all survived greater than twoyears. PSK showed a tendency toward protect-ing against the immunosuppression that typi-cally accompanies surgery and long-term che-motherapy. By the early 1980s, once more re-inforced by the results of Kodama et al,27 theuse of PSK as the immuno-component ofchemoimmunotherapy consistently doubledthe two-year survival rate for stomach cancerin Japan.

In a 1985 double-blind trial with PSKin stomach cancer, patients with Stage III stom-ach cancer were treated with PSK or a pla-cebo post-surgery, without the use of chemo-therapy.28 PSK significantly extended the dis-ease-free period over 80 months, although sur-vival rate was not significantly extended. Theinvestigators criticized their decision to admin-ister PSK so tentatively: 3 grams/day for thefirst two months, 2 grams/day for up to 14months, then 1 gram/day thereafter for the re-mainder of the trial. They speculated their re-sults would have been better had PSK beengiven at 3 grams/day for the duration of thetrial. The only statistically significant adverseeffect from PSK was darkened pigmentationof the fingernails, occurring in four of 77 pa-tients. After two months on PSK in this trial,patient immunocompetence was significantlyimproved, as judged by increased DTH (de-layed-type hypersensitivity) on skin tests andenhanced chemotactic migration of neutro-phils. Interestingly, this group also found PSKwould improve DTH in aged men who hadlowered immunity, but did not have cancer. Asthe trials progressed it became evident thatindividuals with very low immunity were lesslikely to benefit from PSK therapy than wereindividuals with some degree of remainingimmunity.

During the 1980s and 90s, four trialsestablished that PSK improved survival in

Mushroom

Glucans &

Proteoglycans



stomach cancer patients up to five years, in-cluding some patients with advanced Stage IIIand IV cases with metastasis.29-32 Another trialconducted during this period, which enrolledmore than 5,400 participants, had design flaws

that make it useless to inter-pret.33

A 1986 trial byMitomi and Ogoshi was thefirst attempt to separate thePSK-induced increase instomach cancer survival fromthe effects of long-term che-motherapy. Significantly bet-ter five-year survival was re-ported with PSK. Two yearslater, in the Niimoto prospec-tive randomized trial on 579patients,30 another directcomparison of long-term che-motherapy versus long-termchemotherapy with PSK alsoconcluded that PSK contrib-uted significantly to five-yearsurvival (p<0.01). Further-more, patients found to ben-efit most from PSK werethose with invasion and/ormetastasis and those with bet-ter immune competence priorto surgery, as measured byskin DTH tests.

After Maehara’sgroup showed PSK combinedwith chemotherapy can im-prove survival as far as 15years (see Figure 4a),31 theirgroup investigated possibleconnections of PSK-respon-siveness with known immu-nity mechanisms.34 Tsujitaniet al at Kyushu Universityobserved earlier that dendriticcells could infiltrate cancer-ous stomach lesions in theirpatients.34 Further examina-

tion of biopsy material revealed that patientswho achieved extended survival were thosewho exhibited the most marked dendritic cellinfiltration of their tumors prior to surgery.

1009080706050403020100

0 1 2 3 4 5

Immunochemotherapy (n=12)Chemotherapy (n=12)

Years after gastrectomy

Per

cent

Sur

viva

l

1009080706050403020100

0 1 2 3 4 5

Immunochemotherapy (n=20)Chemotherapy (n=9)

Years after gastrectomy

Per

cent

Sur

viva

lFigure 3. Survival rates of stomach cancer patientswith marked dendritic cell infiltration (top) or slightinfiltration (bottom), given either chemotherapyalone or chemotherapy with PSK(immunochemotherapy). From Tsujitani et al, 1992.34



Certain immune cells which resemblemacrophages are located in the skin and virtu-ally all other tissues, and very likely act as anearly warning system for the body’s immunedefenses. Having dendritic or finger-like pro-jections, they are called dendritic cells, unlessthey are present in the skin, where they aretermed Langerhans cells. These immune cellsoften are the first to detect the presence of for-eign antigens and initiate an appropriate re-sponse against them. These cells first ingestthe foreign material, then break it down tosmaller pieces. Subsequently they can“present” the antigens to T-cells, with whichthey habitually interact at close range to co-operatively mount immune responses, includ-ing cytotoxic activity against cancerous tissue.Dendritic-killer cell coordinated responses arethe prototypical mechanism for tumor cell kill-ing.

Further retrospective examination oftissue samples from 53 patients with Stage IIIstomach cancer, of whom 20 had received PSKas immunotherapy, demonstrated that amongpatients manifesting marked tumor infiltrationby dendritic cells at the time of surgery, five-year survival was greater than 90 percent; yetPSK did not significantly enhance survival.Among patients with low dendritic cell infil-tration, five-year survival was a mere 10 per-cent. Thus, of nine such patients subjected toconventional chemotherapy without PSK,none survived beyond three years. Of 20 whoreceived the same chemotherapy regimen withPSK, nine (45 percent) were still alive at threeyears. (see Figure 3) The investigators con-cluded for stomach cancer patients who showlimited dendritic cell infiltration prior to sur-gery, PSK immunotherapy is likely to signifi-cantly increase their chance for long-term sur-vival.

In 1994, The Lancet published the find-ings from a well-designed trial on PSK therapyin the treatment of stomach cancer conductedby the Study Group of Immunochemotherapywith PSK for Gastric Cancer of Japan.32 Che-

motherapy with PSK was compared againstchemotherapy without PSK, and PSK wasagain found to significantly improve both five-year survival and disease-free survival (seeFigure 4b). No toxic effects could be observedfor PSK, “even after meticulous review of allthe patient records.…” Although the exactdegree of benefit from PSK was subsequentlychallenged,35 this trial has great clinical sig-nificance.

PSK and Colorectal CancerAs its benefits to stomach cancer be-

came established, PSK was assessed for itspotential anticancer activity in patients withadvanced colorectal cancer. In an eight-year,double-blind trial, 36 111 patients withcolorectal cancer (pathologic stages III and IV,Dukes Stage C) were randomized into twogroups, then administered PSK or placebo indecreasing doses over time, as per Kondo andTorisu’s earlier gastric cancer study. PSK, 3grams/day, was given until two months aftersurgery, followed by 2 grams/day until 24months, and 1 gram/day thereafter. PSK sig-nificantly improved both the eight-year sur-vival rate (to 40% vs. 25%, p<0.05) and thedisease-free interval (to 25% vs 8%, p<0.05).

In 1992, Mitomi et al, in the Coopera-tive Study Group of Surgical AdjuvantImmunochemotherapy for Cancer of Colonand Rectum, published the results of a largemulticenter trial with PSK in colorectal can-cer.37 They recruited 448 patients from 35 in-stitutions in Japan, randomized them into twogroups, then put them through surgery andchemotherapy plus or minus PSK. After thethird year, PSK had significantly improved sur-vival and the disease-free period in the colongroup (p<0.05 in both)(see Figure 4c), but notin the rectal cancer group (p=0.12).

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Table 2. PSK: Controlled Trials in Other Cancers

Cancer Type Authors Subjects Outcome

Colorectal Torisu, Kondo et al, 199036 111 PSK extended 8-yr survival DOUBLE-BLIND Surgery/no chemo +/-PSK (p<0.05), disease-free

period (p<0.05), enhanced DTH immunity (p<0.05)

Colorectal Mitomi et al, 199237 448 PSK extended colon 5-yr Surgery + chemo +/-PSK survival (p<0.04), disease-

free period (p<0.05); rectal benefits not sig. (p=0.1)

Esophageal Ogoshi et al, 199539 158 PSK extended 5-yr survivalSurgery + radiother. (RT) post- surg+RT+CT (p<0.03);+/- chemother. (CT) normalized serum factors

+/- PSK

Nasopharyngeal Go and Chung, 198941 34 PSK extended 5-yr survival Radiotherapy (p<0.04), but not disease-

+/- chemother. +/-PSK free period

Lung (NSCLC) Hayakawa et al, 199342 185 PSK extended 5-yr survival Stages I-III Radiother. +/-PSK 2-4x, all stages (p<0.005);

tumors <5cm, age >70 yrs more benefit (p<0.04, 0.01)

Breast, ER+/- Toi et al, 199244 914 PSK extended survival in Stage II, IIIA MMC +/- Tamoxifen ER-neg, non-metas. Stage II post-surgery +/- Ftorafur +/- PSK (p<0.002)

Breast, ER+/- Morimoto et al, 199645 889 No evident benefit Stage II MMC+/- Tamoxifen from PSK post-surgery +/- Ftorafur +/- PSK

Breast Iino et al, 1995,46 199747 227 PSK trend to extended 10-yr Stages I, II FEMP chemotherapy survival (p=0.07), 10-yr

+ Levamisole or PSK; disease-free period (p=0.1);compared HLA B40+ HLA B40+ pts. had 100% 10-vs HLA B40- yr survival (p<0.05)

Leukemia/ANLL Ohno et al, 198448 67 Trend to lengthened in remission remission (p=0.1) in pts. with remission >270 days

Leukemia/ALL Kawa et al, 199149 108 No evident benefit from PSK in remission



PSK and Esophageal CancerPre- and post-operative radiotherapy

can improve survival in esophageal cancer. In1980, Okudaira et al reported on a non-con-trolled, retrospective analysis of their successwith combined radiation, chemotherapy, andimmunotherapy in 133 cases.38 They con-cluded the addition of immunotherapy to theregimen using either PSK or OK-432 (animmunopotentiator which has undesirableside-effects) significantly improved both one-year and two-year survival.

In the Cooperative Study Group forEsophageal Cancer in Japan, a prospective,randomized, multi-center study of 158 esoph-ageal cancer patients,39 researchers followedfive-year survival and its relationship to alpha1-anti-chymotrypsin (ACT) and sialic acid(SA) levels. These serum-borne substances areimmunosuppressive at high serum levels, butare sometimes lowered by PSK treatment.After undergoing surgery, followed by radio-therapy, patients were randomly assigned toone of four groups. Two groups received che-motherapy, one with and one without PSK; theother two received no chemotherapy, one withand one without PSK.

After all comparisons were complete,patients who received PSK (3 grams/day forthree months beginning immediately after sur-gery) had a significantly better survival rate atfive years (p<0.03). Those with abnormallyhigh levels of ACT had poor survival unlessthey received PSK (26% vs 55%, p<0.008).The same was true for patients with abnor-mally high SA (31% vs 58%, p<0.07). Thisshows PSK clearly benefits five-year survivalin esophageal cancer and has markedly greaterbenefit for those patients with pre-operativehigh ACT or SA. Ogoshi and other membersof this group previously reported a similarpattern in patients with gastric cancer.

PSK and Nasopharyngeal CancerConventional treatment of nasopharyn-

geal carcinoma has involved radiotherapy,sometimes followed by chemotherapy. In asmall controlled trial carried out in Taiwan,researchers randomly selected 34 patients whohad received radiotherapy, and administeredto 14 of the patients various forms of chemo-therapy, using cisplatinum, 5-fluorouracil,methotrexate, and vincristine. Once this pri-mary therapy was completed (radiation or ra-diation plus chemo-), the entire group was ran-domized to receive PSK (3 grams per day, forup to two years) or not. As shown in Figure4d, the PSK group showed significantly ex-tended survival at five years (28% comparedto 15% for controls, p=0.04). 41

PSK and Lung CancerIn 1977, Hayakawa and colleagues at

the Gunma University School of Medicine inJapan began giving PSK to non-small-cell lungcancer patients post-radiotherapy.42 After es-tablishing radiotherapy was only marginallyeffective in tumors larger than 2 cm in diam-eter, they added immune system potentiationto the regimen. One-hundred-eighty-five pa-tients with epidermoid carcinoma, adenocar-cinoma, or large-cell carcinoma, of severityup to stage IIIB, were enrolled. Each patientreceived radiation therapy 6-7 weeks. Sixty-two were subsequently randomly selected toreceive PSK 3 grams daily, in repeating cyclesof two weeks on and two weeks off. After fiveyears, almost four times more of the patientstreated with PSK were alive (27% comparedto 7% for those not given PSK, p<0.005) (seeFigure 4e).

The benefit to lung cancer patientsfrom PSK in this study is clinically significantin that more-advanced patients with stage IIIdisease who received PSK had a betterprognosis than stage I and II patients who didnot receive PSK. Furthermore, this trial alsodemonstrated PSK given in addition to

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radiotherapy was particularly helpful for olderpatients (>70 years, p<0.007) and patients withsmaller primary tumors (£ 5 cm diameter,p<0.04). When disease stage was factored out,patients who had higher Karnovskyperformance scores prior to receiving PSK alsohad better survival (p<0.02), suggesting thebetter-conditioned lung cancer patient standsto benefit more from PSK.

PSK Selective Effectiveness AgainstBreast Cancer

As early as 1984, Sugimachi’s groupat Kyushu University published a retrospec-tive analysis of breast cancer patients with re-current disease, all subjected to “surgical hor-mone therapy” (total ovary and partial adre-nal gland removal). Some patients then re-ceived chemotherapy with or without PSK im-munotherapy.43 The earliest-treated group(1961-1969) received only surgical hormonetherapy and served as controls. A later group(1970-1976) received mitomycin-C immedi-ately after surgery. An even later group (1970-1981) received long-term combination chemo-therapy along with PSK immunotherapy. Thesurvival rate after recurrence was significantlyextended by the immunochemotherapy, incomparison to the other two groups. The valueof this type of study is limited because thepatient groups are drawn from different popu-lations; nonetheless, the findings are markedand support the use of PSK in breast cancer.

In 1992, a large randomized trial evalu-ated tamoxifen as an addition to the then-con-ventional chemotherapy, and factored in PSK(3 grams daily for two years) as the immuno-therapy arm. This trial involved 914 patientswho were sub-analyzed by: (1) estrogen re-ceptor-positive or negative status; (2) extentof metastatic lymph node involvement; and (3)classic cancer stage (Stages I-IV). In-depthanalysis revealed PSK significantly extendedsurvival in ER-negative, Stage IIA T2N1 pa-tients without lymph node involvement. This

limited finding was later contradicted byMorimoto’s group,45 who also did a large trialand found no statistical evidence of benefitfrom PSK.

This seeming paradox may have beenresolved by Iino et al, working at Japan’sGunma University.46,47 Their 1995 trial onbreast cancer patients with vascular invasionfound strong statistical trends for extended 10-year survival with PSK use (p=0.07), and ex-tended disease-free period (p=0.1). Their datasuggested clinical effectiveness, yet the sta-tistics fell short of formal verification. Know-ing that HLA B40 antigen status had beenlinked to likelihood of survival with breastcancer, the researchers compared their B40-positive patients treated with PSK against B40-negatives. After tissue typing and other requi-site technical protocols, the researchers estab-lished the B40-positive patients who weretreated with PSK (3 grams daily, two one-month courses each year) in addition to che-motherapy had 100-percent survival after 10years,47 as shown in Figure 4f. The statisticalsignificance compared to the no-PSK chemo-therapy group was clear (p<0.05); B40-nega-tive patients treated with PSK had approxi-mately 50-percent survival at 10 years, whichwas not statistically significant. These provoca-tive findings suggest breast cancer patientsmay well benefit from taking PSK in conjunc-tion with chemotherapy. Patients positive forHLA B40 antigen may derive great benefitfrom taking PSK; those who are negative maybenefit little or not at all.

PSK in Leukemias (ANLL, ALL)Acute non-lymphocytic leukemia

(ANLL) can be forced into initial remissionusing aggressive chemotherapy, but remissionis often short-lived.48 In a multi-centerJapanese trial on 67 patients with ANLL whowere initially in remission after combinationchemotherapy, patients were randomized tomaintenance chemotherapy or maintenance



chemotherapy plus PSK 3 grams per day.Maintenance chemotherapy was terminated attwo years and PSK was continued for the studyduration. Survival was followed toapproximately 4.5 years. The statisticalanalysis suggested only a trend toward benefitfrom PSK (p=0.1), which may have been dueto the relatively small number of patientsinitially enrolled and the even smaller numbersurviving at the end. There was a suggestionfrom the data plots that for individuals whoremained in remission for 270 days or longer,PSK might add a further remission of as muchas 418 days. In another study, PSK did notsignificantly benefit children in remission fromacute lymphoblastic leukemia.49

PSK ConclusionWhile PSK is not a panacea for can-

cers, it can improve five-year survival in someindications by as much as double, and perhapsextend survival to as much as 15 years (seeFigure 4). In some patient subsets, such asHLA B40-positive breast cancer, or in the pres-ence of risk factors such as impaired immu-nity or high ACT or SA, PSK can be espe-cially life-saving. PSK also helps conserveimmune status in the face of toxic challengeby conventional treatments.88 After a quarter-century of trials indicating PSK can improvecancer survival, the cumulative human find-ings amount to a recommendation for its in-clusion in standard anticancer protocols. Withits risks for adverse effects virtually nonexist-ent, PSK’s contribution to the benefit-risk pro-files of these protocols can only be positive.

PSP: Coriolus versicolorPolysaccharide-P Extract

PSP (“Polysaccharide-P,” poly-saccharopeptide) is prepared from culturedmycelium of the COV-1 strain of Coriolusversicolor.22,50 PSP may contain as many asfour discrete molecules, all of which are likelyto be true proteoglycans. Chromatographic and

spectral data from infrared nuclear magneticresonance and proton resonance are consistentwith PSP being polypeptide (small protein)moieties with polymeric monosaccharidechains attached.

The polypeptides in PSP resemblethose of the closely-related proteoglycan PSK,in that they are enriched with aspartic andglutamic acids.51 However, PSP differs fromPSK in its saccharide makeup, lacking fucoseand carrying arabinose and rhamnose. Thepolysaccharide chains are true beta-glucans:gas chromatography-mass spectrometry dis-closed mainly 1-4, 1-2, and 1-3 glucose link-ages, together with small amounts of 1-3, 1-4,and 1-6 galactose, 1-3 and 1-6 mannose, and1-3 and 1-4 arabinose linkages. A few alpha-linkages are probably also present. The mo-lecular weight of PSP is approximately100,000 daltons,51 and it is routinely deliveredorally.

Clinical research with PSP has taken afast track since it was isolated in 1983 (for ahistory, see Yang52). With Phase I, II, and IIIhuman trials now completed, PSP has beenproven to be non-toxic,21,53-55 with markedimmunopotentiation capacity sufficient to im-prove survival rate and quality of life in can-cer patients.21,50 The Phase I trial provided PSPat doses up to 6 grams per day for one monthto 16 healthy persons and five breast cancerpatients. Appetite increased in a majority ofthe subjects, and in this and other preliminarytrials no evidence was found for serious ad-verse effects.56,57 The Phase II58 and Phase III59

trials established that PSP benefits patientswith stomach, esophageal, and non-small-celllung cancers, while substantially protectingagainst the unpleasant effects of both the can-cers per se and the toxic therapies convention-ally employed to treat them.60,61

In the Phase II double-blind trial, con-ducted in 1992 at several hospitals in Shang-hai, 274 patients with stomach, esophageal, orlung cancers were dosed with PSP or sharkliver oil (batyl alcohol).62 Patients received

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Figure 4a-f. Clinically significant extension of survival by PSK, in various cancerstreated also using conventional chemotherapy and/or radiotherapy. Top, left:stomach, 5-year.32 Top, right: stomach, advanced, with invasion and metastasis, 15-year.31 Middle, left: colon, 5-year.37 Middle, right: nasopharyngeal, 5-year.41 Bottom,left: Breast, stage II, HLA B40-positive, 10-year.47 Bottom, right: lung (non-smallcell), 5-year.42

Figure 4e.

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Figure 4f.

Figure 4c. Figure 4d.

Figure 4a. Figure 4b.

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conventional anticancer therapies (radio-therapy and/or chemotherapy), following sur-gery where appropriate. The PSP dose was 3.1grams/day, the batyl alcohol 450 mg/day, takenby mouth before meals for two months. Ef-fectiveness was judged by marked improve-ment of clinical symptoms together with; (a)significant improvement in blood profiles(white cell count, other) and/or immune indi-ces; and/or (b) significant improvement inKarnovsky performance status or body weight.If none of these criteria for effectiveness wasmet in a patient at the end of the trial period(six months), the treatment was judged inef-fective.

Once the code was broken at the endof the trial and the data analyzed, PSP wasfound effective for 82 percent of the patientsversus 45 percent for batyl alcohol (p<0.001).PSP improved clinical symptoms overall. PSPalleviated symptoms commonly associatedwith cancer, including fatigue, anorexia, nau-sea, thirst, cold sweat, and pain. PSP also al-leviated the severity of systemic toxic dete-rioration associated with conventional thera-pies, stabilized or increased body weight, andsignificantly improved overall immune status.The extent of benefit to patients with specificcancer types is summarized in Table 3.

The success of the Phase II trial justi-fied progression to a well controlled 17-month,multi-center Phase III trial, which was carriedout at hospitals in Shanghai, Beijing, and otherareas in China, with a total 189 patients. Thedouble-blind study used the same doses andtest materials as the previous study, and ex-amined PSP against the same three cancers co-treated with conventional therapies.59 PSP waseffective in 87 percent of patients, versus 42percent for the shark alcohol (p<0.01), usingthe same criteria for effectiveness as the PhaseII trials.59 Fatigue, loss of appetite, anorexia,vomiting, dryness of mouth or throat, sweat-ing, and pain all were significantly decreased(p<0.05). PSP lessened fatigue in the greatest

number of patients (81 percent) and pain inthe least number (26 percent). PSP also im-proved most of the other parameters measuredin this Phase III trial.59 Karnovsky performancestatus significantly improved in 95 percent ofthe patients (compared to 22% of the controls,p<0.05). White cell count and hemoglobinwere significantly improved, as well asinterleukin-2, which helps activate killer cells.CD4/T-helper counts were conserved morethan in controls, as was the CD4/CD8 ratio.Body weight was maintained and PSP pro-duced no adverse effects.

In the Phase III trial, as well as a num-ber of reports from individual treatment cen-ters, PSP again demonstrated significant ben-efit against three cancers – stomach, esopha-gus, and lung.21,50,63 PSP also ameliorated ad-verse effects to the bone marrow, liver, skin,and cardiovascular and digestive systems seenin batyl alcohol controls.50 Sun et al quanti-fied the adverse side-effects attributable to thechemotherapy and radiotherapy regimens, andfound markedly lower incidence in the PSP-treated group.61

Although the Phase II and III trial de-signs did not include assessment of long-termsurvival benefit, in an open-label, randomizedtrial on esophageal cancer, PSP did signifi-cantly improve one-year and three-year sur-vival.64 In his cogent 1999 review of PSP, Liunoted PSP also has favorable action in patientsreceiving bone marrow transfusion (BMT)treatment.65 Taken together, the findings fromthe Phase II and Phase III trials establish thatPSP benefits cancers of the stomach,62,66-68

esophagus,62,63,69-71 and lung,62,72-76 and PSP hasbeen recognized for these applications byChina’s Ministry of Public Health.

As shown in Table 3, the percentageof patients who experienced benefit from PSPin the Phase II and Phase III trials ranged from90-97 percent for stomach, 82-87 percent foresophageal, and 70-86 percent for lungcancers, all statistically significant when

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Cancer Type Authors Subjects Outcome

Stomach Liu et al, 199362 78 PSP effective 97% pts. vs. 77% DOUBLE-BLIND PSP vs shark oil controls (p<0.01). Marked Phase II trial symptomatic improvement

Stomach Zhang et al, 199389 18 PSP increased NK cells DOUBLE-BLIND PSP vs shark oil (p<0.05) Subgroup Phase II

Stomach Shi, 199390 30 PSP increased NK cells DOUBLE-BLIND PSP vs shark oil (p<0.01) Subgroup Phase II

Stomach Liu et al, 199959 60 PSP effective 90% pts. vs 40% DOUBLE-BLIND PSP vs shark oil controls (p<0.01) Phase III trial

Stomach Wu et al, 199991 82 PSP increased NK, IL-2, OPEN PSP vs shark oil CD4/CD8 ratio (p<0.01)

Esophagus Liu and Zhou, 199362 112 PSP effect. 82% pts. vs. 32% DOUBLE-BLIND PSP vs shark oil (p<0.001). Marked Phase II trial symptomatic improvement

Esophagus Yao, 199964 100 PSP extended 1-yr, 3-yr OPEN Surg + RT +/-PSP survival (p≤0.05)

Esophagus Liu et al, 199959 61 PSP effective 87% pts. vs. 43% DOUBLE-BLIND PSP vs shark oil controls (p<0.01) Phase III trial

Lung Liu and Zhou, 199362 84 PSP effective 70% pts. (>2x DOUBLE-BLIND PSP vs shark oil controls) (p<0.01). Marked Phase II trial symptomatic improvement

Lung Liu et al, 199959 68 PSP effective 86% pts. vs. 42% DOUBLE-BLIND PSP vs shark oil controls (p<0.01) Phase III trial

Gynecological Sun and Zhu, 199960 40 PSP improved quality of life (Ovarian, Chemotherapy +/-PSP (p<0.05) Endometrial)

*Where indicated, conducted within two larger, compounded Phase II and Phase III trials. Herein listed separately for clarity. Statistical data listed as derived by the trial investigators.

Table 3. PSP Controlled Trials Against Various Cancers.



compared against figures for controls. Clearly,PSP can benefit the majority of patientsafflicted with such cancers, and has thepotential to be therapeutic against othercancers as well.73,77

Mushroom Immunoceuticals:Mechanisms of Action

The orally-bioactive glucans andproteoglycans isolated from mushrooms arecurrently the most promising class ofimmunoceuticals. Without doubt, they are ca-pable of simultaneously augmenting all the keypathways of host immunity. After decades ofexperimentation with lentinan, PSK,schizophyllan, and PSP, as many potentialmechanisms have been identified as the manypathways known to exist in the immune sys-tem. Perhaps the single most logical and likelysite of action is in dendritic or Langerhans cells(LC).

Dendritic cells, of which Langerhanscells are a skin-residing subset, are capable ofsensing foreign or domestically-threateningmaterial and mobilizing an appropriate, timelyimmune response. PSK injected directly intohuman stomach tumors prior to surgery wastaken up specifically by dendritic cells locatedin and around the tumors.78 Tsujitani, Maehara,and their coworkers successfully correlated ex-tended survival of stomach cancer patientswith the degree of infiltration of the tumorsby LC.34,79

Due to their widespread localizationthroughout tissues, dendritic cells are the firstcellular line of defense of the immune system.They are likely to be the first host cells to con-tact incoming glucan material. As glucans en-ter the oral cavity, they can be sampled by theLC present in the oral mucosa, and then bydendritic cells in the stomach and intestines.After glucan materials are absorbed and cir-culate to the liver, the dendritic-like Kupffercells can sample them. Glucan material reach-ing lymph nodes can be taken up by dendritic

cells residing in the nodes. Carbon-14 radio-labeling of PSK was utilized to prove its largeproteoglycan molecules are absorbed andreach the bloodstream intact.23

Similar to PSK stimulating dendriticcells, PSP is known to stimulate macrophageor other immune phagocytic activity in vivo.When mice were given charcoal intravenously,then fed PSP, both the phagocytic activity ofcells in the blood and the clearance of the char-coal from the circulation were significantlyaccelerated.80

These “upstream” activation effects ofPSK and PSP on tissue and blood-borne ph-agocytic cells likely account for their “down-stream” effects, which effectively result inheightened anticancer immunity. It is tempt-ing to imagine after being picked up by a den-dritic cell or other antigen-sorting cell, PSKand PSP may function as antigenic stimuli.Perhaps their presence above a certain thresh-old inside a phagocytic immune cell, whileinnocuous to the cell’s survival, in some wayactivates or primes that cell. Perhaps mush-room glucans and proteoglycans act morecrudely, “prodding” the cell to greater antigen-presenting activity.

In killer or pre-killer T-cells, it is pos-sible the close proximity of theseimmunoceutical substances to the outer cellmembrane could result in activation or height-ening of activity. Elevated cytotoxic, killer cellactivity has been linked in vivo to a more posi-tive post-operative clinical course in cancerpatients.81,82 PSK activates killer cells in vivo.The instillation of PSK into a human gastrictumor mass prior to resective surgery causedT-cells around the site to become tumor-infil-trating and develop significantly enhancedcytotoxic “killer” activity directed at the tu-mor. Similar findings were obtained with a 14-day course of PSK in bladder cancer patients.82

PSK also activates human NK cells in cultureat concentrations reached in the blood by nor-mal oral dosing of 3 grams per day.81,82

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PSP also activates killer cells in situ inthe living cancer patient. In the Phase II andIII double-blind trials, PSP significantly raisedNK cytotoxic activity, significantly raised IL-2 levels, and significantly improved the CD4helper/CD8 suppressor T-cell ratio. Altogether,these are the primary components of antican-cer immunity.

Adoptive immunotherapy protocols81

aim to remove potential killer cells from thepatient, activate them with the cytokine IL-2(interleukin-2), then return them to the bodyto attack cancerous tissue. But the IL-2 dosesrequired to trigger activation of CD4 and NKcells can have major adverse side-effects. Con-comitant dosing of such cells with PSP cancut the required amount of IL-2 by at least half.PSP stimulates lymphokine-activated killer(LAK) cell proliferation by itself at relativelylow concentrations and in the absence of IL-2.83 In mice with suppression of IL-2 produc-tion from cyclophosphamide toxicity, PSPsupplementation restored IL-2 production tonormal.51

Another potential avenue of mushroomimmunoceutical action is through elevation ofimmune system cytokines in vivo. PSK, PSP,lentinan, and other mushroomimmunoceuticals can provoke secretion ofcytokines, including IL-1, IL-2, IL-6, IL-8,TNF (tumor necrosis factor) and variousinterferons from cultured immune cells by asmuch as 5-120 times baseline levels.1,2 How-ever, experiments in which antibodies wereused to block the actions of individualcytokines clearly demonstrated cytokines werenot necessary for PSK to activate human natu-ral killer cells.81 This finding points to pos-sible cell-to-cell interactions, rather than phar-macologic cytokine activity, as the main fo-cus of mushroom immunoceuticals. Theformer class of effect would also be more con-sistent with their pro-homeostatic effects,rather than the adverse effects associated withthe use of cytokines in human trials.

A critical assessment of themechanistic findings from human studies ofvarious mushroom immunoceuticals led to the

Colony-stimulating

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Thymus,bone marrow

activation

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competentcell number

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TissueMacrophages

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Figure 5. Likely pathways for immune enhancement by mushroom proteoglycans.Modified, from Chihara et al.8



composite schematic presented in Figure 5.Many details of mushroom immunoceuticalactions are unclear, but their clinical versatilityshould provide impetus for more precisedefinition of their modes of action.

Mushroom Immunoceuticals:Valuable Anticancer Tools

A trend toward integration ofimmunopotentiating agents with the extantcancer regimens of surgery, chemotherapy, andradiation therapy is now considerably ad-vanced in Japan and China – countries wheremushroom preparations have been an antican-cer resource for centuries. In the West, a moreproactive approach to cancer management islong overdue, with the glaring failures of con-ventional modalities to cure common cancersand the availability of good clinical evidencesupporting mushroom immunoceuticals. Mis-placed dogma should soon give way to a newround of clinical and basic research aimed atmelding this immunotherapy approach intoqualitative improvement of cancer survivalrates.

The most frequent cause of shortenedsurvival of the patient with cancer is metasta-sis, occurring with or without invasion of thesurrounding tissues by the formed tumors.Surgery often successfully reduces the tumormass, and chemotherapy or radiation therapysometimes will further reduce detectable tu-mors and minimize invasiveness and metasta-sis. However, these toxic therapies invariablydamage host immunity, and small invasivemasses or malignant cell clumps (as little as100,000 cells or less) predictably survive thebest efforts to eradicate them. With their ca-pacity to mobilize the immune system againstformed tumors as well as metastases, whilelessening the adverse side-effects of conven-tional therapies, mushroom immunoceuticalsshould offer clinically-attractive options to thethinking oncologist.

Mushroom immunoceuticals comparefavorably with classic biological responsemodifiers, such as BCG, OK-432, LAK cells,or purified cytokines such as interferons, tu-mor necrosis factor, or interleukin-2. All theseare capable of causing fever, chills, rash,edema, arthralgia, hypotension, congestiveheart failure, or CNS toxicities.65 Crude yeastcell wall material, currently being representedas beta-glucan concentrates, reportedly cancause fevers and other problems. The standard-ized mushroom glucans and polysaccharide-peptide preparations cause no fever, allergy,or other type of intolerance.2

With the emergence of putative mark-ers by which their likelihood of efficacy canbe monitored – dendritic cell tumor infiltra-tion, killer cell cytotoxic potential in vitro,abnormally-low skin DTH, elevated levels ofACT or SA – these safe and effective mush-room immunopotentiators are prime choicesfor cancer management. In fact, progressivephysicians have been using them for years.Certainly the risk-benefit and cost-benefit pro-files of mushroom preparations are superiorto anticancer pharmaceuticals. Besides beingsafe to take for periods of years, they improveenergy levels in the cancer patient, speed re-generation of damaged bone marrow, supportthe liver,84 reduce side-effects of toxic antican-cer therapies, and generally raise well-being.PSP also offers analgesic action, which canbe beneficial to the cancer patient. Doses upto 15 grams daily have been tolerated long-term without noticeable adverse effects.59

Although it has been less thoroughlyresearched overall than PSK and its long-termbenefits to survival are not yet as firmly estab-lished, PSP is fast gaining respect as an anti-cancer therapeutic. Strictly controlled, double-blind trials demonstrated PSP improves qual-ity of life in more than 70 percent of patientswith cancer. PSP also lessens the adverse ef-fects of other therapies, while potentiating theircurative effects.50,85 For practitioners hesitantto put full faith in PSP due to its relative lack

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of survival data, the use of a combination ofPSP with PSK might be worthy of consider-ation.

The enhanced survival rates achievedby PSK for several cancers are certainly clini-cally meaningful. Used singly or in combina-tion, PSK and PSP have the potential to ex-tend survival. It may prove instructive, for pro-ponents and skeptics alike, to conduct an inte-grative cancer trial in which mushroomimmunoceuticals play a central role, alongwith digestive enzymes, thymic extract, vita-min C, coenzyme Q10, omega-3 fatty acids,and other positive-acting immunoceuticals.

Glucan and proteoglycan mushroomimmunoceuticals offer hope for cancer pa-tients. These substances are pro-homeostatic,uniquely effective immune boosters, whichpose no threat of autoimmune backlash. Asdietary supplements, they are safe, clinicallyproven, and exhibit near-perfect benefit-riskprofiles. Mushroom immunoceuticals are apotential boon to individuals afflicted withcancer, living with impaired immunity, ormerely descending into ill health with the pass-ing of time.

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13. Nakano T, Oka K, Hanba K, et al.Intratumoral administration of sizofiranactivates langerhans cell and T-cell infiltrationin cervical cancer. Clin ImmunolImmunopathol 1996;79:79-86.

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The Use of Mushroom Glucans and Proteoglycans in Cancer Treatment