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Maitake
D-Fraction:
Apoptosis
Inducer and Immune Enhancer
By
Sensuke Konno, Ph.D
(This
information is taken from Excerpts from Dr. Konno's Article on
Maitake D-Fraction published in Alternative &
Complementary Therapies, April 2001)
Maitake,
The King of Mushrooms
Maitake
is indigenous to Northern Japan.
For hundreds of years, this rare and tasty mushroom has
been praised by traditional Japanese herbalists.
Maitake literally means, "dancing mushroom."
8 Maitake is a
giant mushroom that often reaches 20 inches in diameter an
that may weigh up to 100 pounds.
Such unique characteristics and potential health
benefits are why it is often considered the "king of the
mushrooms." Maitake
is still one of the most valuable an expensive mushrooms in
Japan today.
Maitake
mushroom has been available via cultivation since the
mid-1980's, enabling mycologist and pharmacologists to study
the medicinal properties that have been claimed in anecdotes
and folklore regarding this mushroom. Numerous physiologic benefits of maitake have been
postulated, ranging from antitumor, effects to treatment for
hypertension, diabetes, hypercholesterolemia, obesity and
hepatitis B infection. 3-7,9-12
Maitake's
antiviral activity against human immunodeficiency virus
(HIV)/auto-immune deficiency syndrome (AIDS) was confirmed by
the U.S. National Cancer Institute in 1992.
Maitake
D-Fraction
Most
research on maitake has been focused on the use of maitake
D-fraction for treatment of various malignancies.
The bioactive D-fraction that is extracted from maitake
is the protein-bound polysaccharide compound and is prepared
by a standardized procedure developed by Maitake Products,
Inc. (Ridgefield, New Jersey).
Among the various maitake fractions that have been
prepared, D-fraction was found to be the most potent for
enhancing the immune system via oral administration or
injection, (effective regardless of route of administration)
leading to the highest reduction rate in cancer proliferation. 14-16
D-fraction
as an Immune Booster
Maitake
D-fraction has been shown to have an antitumor effect on
tumor-bearing mice, 14 with enhanced cytotoxic activity of
macrophages and elevated production of interleukin-1 leading
to the activation of cytotoxic T-lymphocytes (CTSs). 17.
These findings are highly suggestive that D-fraction
acts not only via direct activation of various immune
effectors (macrophages, CTLs, natural -killer (NK) cells, etc)
targeting tumor cells but also via potentiating the
activity/production of various lymphokines.
Thus D-fraction appears to have a potent
immunostimulatory activity, which may account primarily for
its anti-tumor effect on cancer cells.
D-Fraction
as an Apoptosis Inducer- Prostate Cancer
Prostate
cancer is the most common malignance with high mortality in
elderly men in the United States. In 1999, cancer statistics
noted that approximately 140,000 new cases and more than
39,000 deaths were expected to occur annually. 19
"Because
of the total failure of chemotherapy treatment of prostate
cancer, an improved efficacy of chemotherapy is urgently
required." 22
This high
mortality is attributable primarily to disease progression to
a hormone-refractory or androgen-independent cancer state.
…Unfortunately current conventional therapies for
hormone-refractory prostate cancer are ineffective. 22
Androgen
ablation, brachytherapy (radioactive seeds implanting), and
chemotherapy are viable therapeutic options but have not been
able to achieve the expected level of efficacy.
To
explore a more effective modality for treatment of prostate
cancer, a research group from the Department of Urology at New
York Medical College (Valhalla, New York), has recently
conducted a study on the ability of maitake D-fraction to
induce apoptosis activity against human prostatic cancer PC-3
cells (the most aggressive and metastatic cancer cells) in
vitro. 23
Experiments
were performed, including a dose-response study and
examinations of potentiation with Vitamin C and
chemosensitizing effect on anticancer drugs.
The
Results:
Potent
Apoptosis-Inducing Activity
When PC-3
cells were treated with D-fraction at a concentration of 480
ug/ml, almost complete cell death (>95%) was observed in 24
hours, accompanied by "cell blebbing" (vesicle
formation) and considerable damage in the plasma membrane
assessed by lipid peroxidation assay.
These cellular alterations are indicative of oxidative
stress (generation of oxygen free radicals), which appears to
subsequently to cause discrete DNA fragmentation in cancer
cells. Histologic
(in situ hybridization) and molecular analysis then confirmed
that cell death induced by D-fraction had resulted most likely
from apoptosis suggesting that the D-fraction is a potential
apoptosis inducer.
Synergy
with Vitamin C
As little
as 30-60 ug/mL (one sixteenth to on eighth of 480 ug/mL) of
D-fraction combined with 200uM of vitamin C was found to b e
nearly as effective as 480 ug/mL of D-fraction alone,
resulting in a >95% cell death.
It has been reported anecdotally by a number of doctors
and patients that D-fraction appeared to work very well
(cooperatively) with vitamin C.
Such synergy has now been evidenced in this study.
Chemosensitizing
Effect
It was of
additional interest to explore a possible chemosensitizing
effect of D-fraction on anticancer drugs that are currently in
use. Because of
the total failure of chemotherapy in the treatment of prostate
cancer, 22, an improved efficacy of chemotherapy is urgently
required. Compared
to approximately a 50% reduction in cell viability induced by
carmustine (a common Chemotherapeutic agent used in brain
tumor treatment) alone, approximately a 90% reduction in
viability was attained when 60 ug.mL of D-fraction was
combined with carmustine.
This study implies that D-fraction may also have a
chemosensitizing activity on certain anticancer drugs, helping
to improve the efficacy of chemotherapy.
D-Fraction
as a Metastasis Inhibitor
Inhibition
of cancer metastasis is another critical issue in the slowing
down of cancer progression or prolonging the survival time.
This aspect of cancer treatment was addressed in a 1995
study of maitake D-fraction.25 The results suggest that
maitake preparations are capable of preventing tumor
metastasis, presumably by necrotizing tumor cells present in
the blood and /or lymphatic vessels via the activated
immune-competent cells.
Clinical
Trials in Human Subjects
Although
a number of animal studies have confirmed maitake's ability to
inhibit cancer, not many human trials have yet been conducted.
To test whether the efficacy of D-fraction demonstrated
on animals 14,15 could be verified in patients with cancer, a
non-randomized clinical study was conducted on 165 patients
(25-65 years old) with various types of advanced cancers.
The results
showed that tumor regression or significant symptomatic
improvements with D-fraction were observed in 73% of patients
with breast cancer, 67% of patients with lung cancer, and 47%
of patients with liver cancer.
When D-fraction was given with chemotherapy, the
response rates improved from 12% to 28%.
Overall,
the following trends were found: the clinical status of
patients with breast, prostate, lung, and liver cancers was
improved significantly with D-fraction, while the D-fraction
was less effective on subjects with bone and stomach cancers
or with leukemia.
It is
important to note that many side effects of chemotherapy on
all patients with all types of cancers were ameliorated when
D-fraction was given with conventional treatment.
Adverse
symptoms, such as nausea, hair loss, and leukopenia, were
alleviated in 90% of the patients in the study.
A reduction in pain was also reported in 83% of the
study patients.
Based on
the above studies and the in vitro prostate cancer study, it
is conceivable that maitake D-fraction may work cooperatively
with chemotherapy, implying that D-fraction should be
considered as a valuable adjuvant in ongoing cancer
chemotherapy.
Effects
of D-fraction on HIV/AIDS and Kaposi's Sarcoma
Both the
National Institute of Health in Japan (Tokyo) and the U.S.
National Cancer Institute (Bethesda, Maryland) have confirmed
that maitake D-Fraction was able to prevent the HIV-mediated
destruction of T-helper lymphocytes up to 97% in vitro.13
These
findings suggest that D-fraction may even help to prevent of
slow down the progression of HIV to full-blown AIDS.
Several physicians who used D-fraction for the
treatment of patients with HIV/AIDS have also reported that
oral administration of D-fraction had significantly improved
the clinical conditions of patients with Kaposi's sarcoma
(even those who were undergoing radiotherapy and other
AIDS-related symptoms.26
Toxicity
The
FDA has exempted D-fraction from a phase I study of toxicology
Maitake
D-fraction (liquid form) and maitake tablets (whole crude
powder) were tested on mice to assess potential toxicity. 18
Based on
a pilot study indication the optimal dose of 1 mg/kg of
D-fraction for antitumor activity, a ten-times-higher dosage
was given to mice for 30 days.
On the thirty-first day, no abnormal symptoms or signs
were observed when mice were killed and their organs and blood
thoroughly examined.
Similar
tests were repeated using maitake tablets and essentially the
same results as the D-fraction tests were obtained with no
toxic or adverse effects. The researchers concluded that both maitake D-fraction and
tablets are safe with no toxicity.
Indeed, such safety is supported further by the fact
that the FDA has exempted D-fraction from a phase I study of
toxicology. 26
FDA
Approval of the IND for D-fraction for Breast and Prostate
Cancers
In 1998,
the Food and Drug Administration (FDA) granted Maitake
Products, IN (Paramus, New Jersey), an investigational new
drug application (IND) to conduct a phase II pilot study using
maitake D-fraction on patients with advanced breast and
prostate cancers. These
studies are currently underway at Metabolic Associates
(Florham Park, New Jersey) to evaluate the immune stimulatory
effect of D-fraction on tumor size, tumor makers, immune
assays, clinical symptoms, and quality of life of patients.
Other independent institutions are also planning to
conduct similar trials.
Recommended
Maitake Dosage
Fukumi
Morishige, M.D., Ph.D, a renowned Japanese surgeon and a
member of the Linus Pauling Institute, Corvallis, Oregon,
explains that taking small amounts of vitamin C along with the
mushroom supplements will facilitate absorption of
polysaccharides and enhance their effectiveness further.27.
Such increased absorption renders polysaccharides more
accessible to immune cells, including macrophages and NK
cells. As,
mentioned earlier, the synergy with vitamin C was also
demonstrated by the study on maitake D-fraction-induced
apoptosis in prostate cancer PC-3 cells. 29
The
following dosages of maitake D-fraction and maitake tablets
for adults are recommended. (but not established)
• 1-4
per day of maitake tablets for prevention and 4-7 grams for
therapeutic self-help. (e.g. for patients with chronic immune
dysfunction).
• 5-6
drops of maitake D-fraction (GrifronPro D-fraction®; Maitake
Products, Inc.) 3 times per day, for health maintenance and
15-20 drops, 3 times per day for therapeutic purposes.
•
Optionally, 250-1000 mg of Vitamin C can be taken with maitake
D-fraction or tablets as described above.
Note:
Please, consult your physician/healthcare professional as to
what dosage you should be taking for your condition.
To
learn more about this natural healing agent, see Maitake.com.
References
3.Mizuno,T.
et al. Maitake, Grifola frondosa; Pharmacological effects.
Food Rev. Int. 11:135-149, 1995.
4. Preuss,
H. et al. Syndrome X, hypertension, and maitake mushroom. Int
I Integrative Med. 1:42, 1999.
5. Kubo,
K., et al. Anti-diabetic activity present in the fruit body of
Grifola frondosa )maitake). Biol Pharm Bull 17:1106-1110,
1994.
6. Kubo,
K., Nanba, H. The effect of maitake mushrooms on liver and
serum lipids. Altern Ther Health Med.2:62-66, 1966.
7. Jones,
K. Maitake: A potent medicinal food. Alternative &
Complimentary Therapies 4:420-429, 1998.
8.
Lieberman, S, et al. Maitake, King of Mushrooms: A Keats Good
Health Guide. New Caanan, CT: Keats Publishing, 1997.
9. Kabir,
Y., et al. Effect of shiitake and maitake mushrooms on blood
pressure and plasma lipids of spontaneously hypertensive rats.
I Nutr Sci 33:341-346, 1987.
10. Adachi, K., et al. Blood pressure lowering activity
present in the fruit body of Grifola frondosa. Chem Pharm Bull
36:1000-1006, 1988.
11. Nakai,
R. et al. Effect of maitake (Grifola frondosa) water extract
on inhibition of adipocyte conversion of C3H10T1/2B2C1 cells.
I Nutr Sci Vitaminol (Toyko) 45:385-389, 1999.
12. Wu,
S., et al. Therapeutic effect of Grifola Polysaccharides in
Chronic hepatitis B (abstr.I. International Programme and
Abstracts. International Symposium on Production and Products
of Lentinus Mushroom, Quingyan, Zhejiang, China, November,
1-3, 1994.
13.
Developemental Therapeutics Program, National Cancer
Institute. In-vitro anti-HIV drug screening results.
NSC: F195001, Jan. 1992.
14.
Hishida, I., et al. Antitumor activity exhibited by orally
administered extract from fruit body of Grifola frondosa
(maitake). Chem Pharm Bull, 36:1819-1827, 1988.
15.
Nanba, H. Antitumor activity of orally administered D-fraction
from maitake mushroom, I Naturopathic Med. 1:10-15, 1993.
16. Ohno,
N., et al. Structural characterization and antitumor activity
of the extracts from matted mycelium of cultured Grifola
frondosa. Chem Pharm Bull 33:3395-3401, 1985.
17.
Adachi, K., et al. Potentiation of host-mediated antitumor
activity in mice by B-glutan obtained from Grifola frondosa
(maitake). Chem Pharm Bull 35:262-270, 1987.
18.
Nanba, H. Maitake D-fraction: Healing and preventive potential
for cancer. I Orthomol Med 12:43-49, 1997.
19.
Landis, S.H., et al. Cancer statistics, 1999. CA Cancer I Clin
49:8-31, 1999.
20.
Mahler, C., et al. Management of relapsing disease in prostate
cancer. Cancer 70:329-334, 1992.
21.
Davis, P., et al. Regulation of prostate growth. I Endocrinol
131:5-17, 1991.
22. Kreis,
W. Current chemotherapy and future directions in research for
the treatment of advanced hormone-refractory prostate cancer.
Cancer Invest 13:296-321, 1995.
23.
Borchers, A.T., et al. Mushrooms, tumors, and immunity. Proc
Soc Exp Biol Med 221:281-293, 1999.
24.
Berges, R., et al. Programming events in the regulation of
cell proliferation and dealth.
Clin Chem 39:356-361., 1993.
26.
Maitake D-fraction obtained IND for clinical study
(corporation publication). Paramus, NJ; Maitake Products,
Inc., Feb. 1998.
27.
Morishige, F. The role of vitamin C in tumor therapy (human).
IN: Meyskens, F.I. Jr. , Parasad, K.N. (eds). Vitamins and
Cancer; Human Cancer Prevention by Vitamins and
Micronutrients. Clifton, NJ; Humana Press, 1986. pp. 399-427.
29.
Guidance for Grifron products for health professionals
(corporation publication). Paramus, NJ; Maitake Products,
Inc., 1997.
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