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Lentinan

Scientific Name(s): Lentinula edodes (Berk.) Pegler.
Common Name(s): Forest mushroom, Hua gu, Pasania fungus, Selected Vegetables, Shiitake, Snake butter, Sun's Soup

Clinical Overview

Use

Lentinan is used widely in Japan and China as an adjuvant to cancer chemotherapy. It is also used for upregulating the immune system; however, the number of quality clinical trials and studies published in English language, peer-reviewed journals is limited.

Dosing

The isolated polysaccharide lentinan from shiitake culture has been used intravenously (IV) at doses of 2 to 10 mg on a weekly schedule as adjunctive therapy for HIV as well as for cancer, primarily in Japan. Oral shiitake extract was used in a trial for the treatment of prostate cancer at 8 g/day for 6 months.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None reported.

Adverse Reactions

Clinical trials report few adverse events at normal dosages. Case reports exist of allergic/contact dermatitis, asthma, rhinitis, and hypersensitivity pneumonitis in shiitake workers. Shiitake dermatitis has been described as a reaction to the ingestion of raw or partially cooked mushrooms and may be a toxic reaction to lentinan. Photosensitivity reactions have also been reported. Anaphylaxis, granulocytopenia, and elevated liver enzymes were reported after rapid (10 minutes) IV infusion in an HIV trial.

Toxicology

The shiitake mushroom is edible and has generally not been associated with toxicity. In a study in mice, high-dose shiitake resulted in increases in plasma bilirubin and plasma creatine kinase.

Botany

Lentinan is a polysaccharide derived from the vegetative parts of the edible Japanese shiitake mushroom. It is the cell wall constituent extracted from the fruiting bodies or mycelium of L. edodes. The light, amber fungi are found on fallen broad-leaf trees, such as chestnut, beech, or mulberry. They have decurrent, even, or ragged gills, a stem, and are covered with delicate white flocking. Shiitake mushrooms are commonly sold in food markets in Asia and are now widely available in the United States, Canada, and Europe.1 Synonyms include Cortinellus edodes, Armillaria edodes, Cortinellus shiitake, and Tricholomopsis edodes.

History

Shiitake has been recognized in Japan and China as a food and medicine for thousands of years. Lentinan was isolated from edible shiitake mushrooms used in traditional Asian cooking and herbal medicine. Extracts of these mushrooms are now being incorporated into over-the-counter dietary supplements designed to improve the immune system.1

Chemistry

The shiitake mushroom contains starch, fiber, chitin, and high amounts of protein.2 Lentinan is a water-soluble, high molecular weight polysaccharide in a triple helix structure, containing only glucose molecules with mostly (1-3)-beta-D-glucan linkages in the regularly branched main chain with 2 beta (1,6)-D-glucopyranoside branchings for every 5 beta-(1,3)-glucopyranoside linear linkages.1, 3 Lentinan, which is thermolabile4 is found in very low concentrations in fresh shiitake mushrooms (approximately 0.02%); at least 5 additional polysaccharides have been isolated from L. edodes.5

Other constituents of interest found in the mushroom include the antioxidant phenolic compounds gallic acid, protocatechuic acid, and catechin6; as well as eritadenine7, 8 selenium (as selenomethionine)9 ergosterol, vitamin D, and calcium.10, 11

Uses and Pharmacology

Cancer

Lentinan has demonstrated inhibition of tumor growth and stimulation of apoptosis in animal experiments and in vitro studies. Increased survival times and improved quality of life have also been reported. However, the number of quality clinical trials and studies published in English language, peer-reviewed journals is limited.12, 13, 14 Lentinan is approved in Japan as a pharmaceutical product and is commonly used as an adjuvant for the treatment of certain cancers in Japan and China.12

Animal data

Animal and in vitro studies show significant antitumor and antimetastatic activity of lentinan5, 15, 16, 17, 18, 19, 20, 21, 22 increased longevity3 and synergism with other chemotherapeutic agents.23, 24, 25

Clinical data

Case reports and open-label, nonrandomized studies form the bulk of evidence for lentinan in cancer therapy, with many of these studies being conducted in Japanese populations and commonly in combination with other therapies.26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 Data are insufficient to recommend clinical applications for lentinan but are sufficient to warrant further large scale, quality trials.12, 13 Clinical trials with negative results (ie, no effect in prostate cancer) have been published.13, 40 Resistance to lentinan chemo-immunotherapy has also been reported.41

In a controlled clinical trial (n = 50), the addition of lentinan (1 mg in 250 mL normal saline given every other day) to a traditional tegafur chemotherapy regimen (1,000 mg/day x 5 days) significantly improved general condition, signs and symptoms, and quality of life in patients with esophageal cancer. Although each of these measures improved in both the control and treatment groups, the effects were greater in the lentinan group (P < 0.01). Clinical efficacy became greater after the 2nd course of lentinan combination therapy compared with tegafur alone (P < 0.0031). Serum cytokine levels also changed significantly more with lentinan (P < 0.05).67

A 2009 meta-analysis of individual patient data compared effects of chemotherapy regimens with and without the addition of lentinan in patients with advanced unresectable or recurrent gastric cancer; studies using lentinan food products and not the pure drug were excluded. Data from 650 patients collected from 5 trials revealed a 25-day better median survival time in patients receiving chemotherapy plus lentinan versus chemotherapy alone (hazard ratio = 0.8; stratified log-rank P-value = 0.011). Most of the trials reviewed were conducted in the late 1980s.68

Immune system effects

Lentinan and other beta-glucans have demonstrated immunomodulatory properties in animal experiments and in vitro studies. Multiple pathways have been described for the effects observed in the immune system, including upregulation of T-cell, cytokine, monocyte, tumor necrosis factor, natural killer cell, complement activation and other macrophage responses.22, 27, 30, 32, 44, 45, 46, 47, 48, 49, 50, 51

Animal data

In mice pretreated with lentinan, significant reductions in parasitemia and increased survival were demonstrated against malaria.52 Similar results were found in rabbits with induced septic insult and other microbial infections.53An increased antibody titer was demonstrated in vaccinated chickens treated with sulfated lentinan for 3 days.54 Other studies report on enhanced antitumor activity by lentinan-induced multiple immune mechanisms3 but note that in vivo effects are more difficult to demonstrate than in vitro.43

Clinical data

Greater changes in serum cytokine levels occurred in esophageal cancer patients treated with lentinan plus traditional chemotherapy (tegafur) than with tegafur alone in a controlled clinical trial (n = 50). Pro-inflammatory cytokines interleukin (IL)-2, IL-6, and IL-12 levels increased, while anti-inflammatory IL-4, IL-5, and IL-10 decreased. These changes became greater following the 2nd course of therapy reflecting an up-regulation of the immune response.67

Other effects

Antimicrobial effects

A wide in vitro spectrum of activity against human pathogens has been described, including activity against staphylococcus aureus, methicillin-resistant staphylococcus aureus, 43300 and ciprofloxacin-resistant Pseudomonas strains.55 Antiviral activity has also been evaluated in vitro against HIV and vesicular stomatitis virus.56, 57, 58, 59

Cholesterol-lowering

Animal experiments have shown varying results.8, 60, 61 An effect on the lipid profile has been attributed to the ergosterol and eritadenine constituents found in the mushroom. Clinical studies are lacking.

Osteoporosis

The vitamin D and calcium content of shiitake mushrooms can be enhanced during cultivation by the addition of egg shells to the growing media and growth under ultraviolet light.10, 11 Animal experiments have shown increased femur and tibia mineralization, increased serum calcium and increased duodenal and renal calcium transport genes with enhanced shiitake diets.10, 11

Dosing

Lentinan is a high molecular weight polysaccharide, and is usually administered by the intraperitoneal route because of poor oral bioavailability and rapid metabolism.12, 14

The isolated polysaccharide lentinan from shiitake culture has been used IV at doses of 2 to 10 mg on a weekly schedule as adjunctive therapy for HIV as well as for cancer, primarily in Japan.58

Oral shiitake extract was used in a trial for the treatment of prostate cancer at 8 g/day for 6 months without significant effect on the disease progression.40

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.13

Interactions

None reported.12

Adverse Reactions

Clinical trials report few adverse events at normal dosages.12, 15, 62 Severe events were reported (anaphylaxis, granulocytopenia, elevated liver enzymes) after rapid IV infusion in HIV patients.58

Case reports exist of allergic/contact dermatitis, asthma, and rhinitis in shiitake workers8, 63 as well as hypersensitivity pneumonitis.64 Shiitake dermatitis has been described as a reaction to the ingestion of raw or partially cooked mushrooms and may be a toxic reaction to lentinan.4, 65 Positive skin prick tests have been described in patients with shiitake-related protein contact dermatitis.63 Photosensitivity reactions13, 14 and GI upset have also been reported.66

Toxicology

The shiitake mushroom is edible and has generally not been associated with toxicity. In a study in mice, high-dose shiitake resulted in increases in plasma bilirubin and plasma creatine kinase.8

In animals, lentinan shows little toxicity. In mice, the lethal dose (LD50) is greater than 1,500 mg/kg (intraperitoneally).5

References

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