Studies

[Yun Zhi = Essence of Mushroom = PSP]

 

(Extracted from: "History, Present Status and Perspectives of the Study of Yun Zhi Polysaccharopeptide (PSP)", Qing-yao Yang, Shanghai Teachers University, 100 Guilin Road, Shanghai, 200234; published by Hong Kong Association for Health Care Ltd.)

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Yun Zhi and Ling Zhi were generally called Zhi in ancient times. They were both Chinese traditional medicinal. Li Shi-zhen in Ming Dynasty classified Zhi into 6 types. Ling Zhi was categorized to red Zhi or violet Zhi and Yun Zhi to Black Zhi or Blue Zhi. The therapeutic effects of Zhi has been verified clinically for thousands of years. In the first Compendium Medica "Shen Non Compendium Medica" published at 2000 years ago, Zhi was regarded as a godly medicine. The Compendium Medica concretely described the therapeutic effects of Zhi as: invigorating men’s vigor and body fluid and favouring longevity after prolonged medication.

STUDY HISTORY

The development of this Chinese traditional medicinal material into a ready traditional Chinese medicine (TCM) product was first initiated in the Northeast Teachers University of China in 1978. It was later developed into an anticancer drug by Kureha Company in Japan following an accidental happening. The neighbor of a pharmaceutical engineer of this company suffered from late stage gastric cancer and was rejected by hospital for treatment. However, after taking the local folk recipe (polyporales, a kind of fungus drug) for several months the patient was cured and went to work again. This miracle encouraged him to make up his mind to identify the anticancer substance from the medicinal fungi. Thus, 200 species of polyporales family were screened and the best strain of Yun Zhi selected which eventually was developed into a new anticancer drug,Krestin (PSK). The raw material of Yun Zhi was not derived from the wild Yun Zhi fruit body, because the wild fungi were always mixed with heterogeneous fungi and its quality could not be guaranteed. The artificial culture of Yun Zhi fruit body was not used either, because the anticancer ingredient of PSK was present in the protein bound polysaccharide in the deep layer cultured mycelia of Yun Zhi.

The success in the research of PSK shocked the tumor-related medical and pharmaceutical communities. In the 14th International Chemotheraphy Symposium, 68 papers of PSK were presented which accounted for 19% of the total number of the papers. In 1980’s the sale amount of PSK was successively ranked on the top among all the medicines in Japan. The success in the research and manufacture of PSK tells us that the traditional Chinese medicine (TCM) is a treasure house but the traditional medicinal materials must be modernized and dealt with in a scientific way.

In 1984, I started to undertake the study of the deep layer cultivation of the mycelia of Yun Zhi and was determined to develop PSK for our own in China.

In spite of the fact that we initiated our step late, we own 2 advantages: First, China has a rich resources of fungi. From 1984-1987 we rapidly and successfully collected and isolated 80 strains of Yun Zhi. By means of double-plate thin layer chromatography developed by ourselves, we comparatively determined the contents of polysaccharopeptide, from which we screened and selected the premium strain Cov-1. Secondly, we own the deep layer cultivation technique which was awarded the Gold Medal Prize in our Chinese Invention Exhibition. With this technique we could carry on the deep layer cultivation of the mycelia of Yun Zhi with a production rate 3 times higher than that of PSK in Japan. Besides, we accidentally found that the B fraction with the most potent anticancer activity present in the Yun Zhi protein bound polysaccharide extracted by means of fractional precipitation with alcohol was higher in concentration than that in the protein bound polysaccharide obtained by salt fractionation in Japan.

According to the studies done by Zhou, J.X.; Chen, R.T. and Yang, M.P. et al., separately, the inhibitory activity of our product on 388 leukemia, sarcoma-180 and HL-60 cells were all higher than that of PSK. Besides, the polysaccharide component of our product contains arabinose and rhamnose with pharmacological actions, such as analgesia and improvement of appetite which has not been reported for PSK. Therefore, the component extracted by us is named Yun Zhi polysaccharide peptide, abbreviated as PsP. In 1989 we accepted the suggestion by S.C. Jong et al. to combine the two words, polysaccharide and peptide, into one, polysaccharopeptide, abbreviated as PSP.

In January 1987, PSP passed the appraisal by scientific achievement association with the conclusion that "PSP study has filled the blank for this category of medicines in China". PSP was later given a series of awards by China and Hong Kong. In 1999 PSP was approved to be included in the list of medicines reimbursable by the government medical insurance and labour medical insurance. Thus, the research and manufacture of PSP have been accomplished after a period of 15 years.

THE PRESENT STATUS OF STUDY

1. A strict quality control standard has been set up for PSP

PSP could not be accepted by the global market without a high standard. Thus, we have stipulated the physio-chemical quality control for PSP which are higher than those of Japanese PSK with the addition of characteristics detection of protein bound polysaccharide. The samples are required to get through the DEAE cellulose adsorption and Sephadex G100 column chromatography. It is also required that in addition of detection for the presence of sugar, peptide has also to be present simultaneously and both are not separable. However, in the ordinary polysaccharide products, even if certain other peptides or proteins are mixed in, their sugar and peptide components appear in different effluents. In HPLC analysis, the sugar and peptide peaks appear with far distance between each other, while the sugar and peptide peaks of PSP always overlap. Therefore, PSP is a polysaccharide and polypeptide complex rather than a mixture of both.

Since the physiological activity of polysaccharide is associated with its molecular weight and polysaccharide less than 5 kd has no physiological activity. Because of this, we have established the HPLC technology for detection of the molecular weight of PSP by referring to the standard of heparins in the British Pharmacopeia, because there was no knowledge of it previously for the quality control of polysaccharide products in TCM. Since then the Chinese Public Health Ministry has required that all the polysaccharide products in TCM have to adopt the PSP method for monitoring of molecular weight.

In addition of application of PSP as an adjunctive treatment for cancer patients, it can also be used as a dietary supplement health strengthening among the healthy and sub-healthy population. For this purpose we have added a criterion to limit the heavy metal content in the quality control of Yun Zhi essence. By means of reverse chelation technique, the Pb, Hg, Cr, Sn, Cu, Cd and AS2O3 contents in the present products of Yun Zhi essence are detected to be lower than those required for the food hygienic allowance in other countries. By this way PSP has been rendered not only as a State grade drug but also a safe and non-toxic high class health food.

2. PSP: a green drug eliminating evil forces without affecting the positive forces

In spite of the fact that Yun Zhi has been regarded as a superb drug since the ancient times, we did not neglect the general toxicological studies for it. The results showed that acute, subacute, chronic, subchronic, genetic, reproductive and fetal toxicity tests were all "negative" or comparable to those of "normal saline". Nor was there any adverse reactions observed in phase I, II clinical trials. PSP has definite cytotoxic action on the cancer cells from gastric and pulmonary cancers, nasopharyngeal carcinoma, cervical carcinoma as well as tumor cells from P388 leukemia, Ehrlich ascitis, Lewis lung cancer and myeloma in animals. PSP has a selective cytotoxic action on cancer cells only without affecting the normal cells at the same dose level, confirmed by a comparative study between lung cancer cells and lung fibroblasts or between the hepatic cancer cells and hepatocytes, thus, PSP can eliminate the evil force without involving the positive forces.

3. PSP is a biological response modifier (BRM) substance playing a special role in cancer treatment

PSP can induce the proeduction of a and b interferons by mononuclear white blood cells, activate the activities of anti-cancer cells, such as macrophages, NK cells. LAK cells and TIL cells, increase the synthesis of the immune factors like IL-2, IL-6 and TNF, block the atrophy of thymus gland in tumor-bearing animals, antagonize the immuno-suppression induced by chemotherapeutic drugs and accelerate the recovery of damage of hemopoetic cells induced by X ray. Thus, the use of BRM is a new measure for the treatment of cancer.

The application value of PSP is as follows:-

a. It can markedly increase the quality of life in cancer patients

The results of phase II and III clinical trials showed that addition of PSP to radio- and chemotherapy for cancer patients can greatly improve their clinical symptoms, raise their Karnofsky’s value, protect the blood picture, potentiate and stabilize their immune function, thus greatly improve their quality of life. The question arises why the research of anticancer drugs is far more advanced but the outcome of anticancer therapy is less desirable in western countries in comparison with those in eastern countries, including China and Japan? For example, among the 10 anticancer drugs most widely used in Japan in 1989, the No. 1, 2 and 8 drugs are all BRM drugs. In brief, removal of evil force with damage on the positive force is not acceptable. Potentiation of the positive force and elimination of the evil force are the essence of traditional Chinese medicine.

b. Detoxication of chemo- and radiotherapies

Chemo- and radiotherapies are the main therapeutic measures in the treatment for moderate and advanced stages of cancer. Due to their severe side effects, approximately ¼ chemotherapeutic agents used always induce iatrogenic diseases. We have compared the adverse reaction scores in 650 cases receiving phase III clinical trials for PSP, between the treatment and the control groups and before and after PSP treatment, following the 20 criteria stipulated by WHO for assessment of adverse reaction to anticancer drugs. The results showed that integrated scores after treatment in PSP group was markedly lower than that of the control group and also lower than that before treatment. Thus, PSP could obviously reduce the adverse reactions induced by chemo- and radiotherapy and combination of chemo- and radiotherapy with PSP could provide a toxicity free or low toxic chemo- or radiotherapy.

c. Enhancement of immunity and reduction of secondary infection

The immune functions in patients receiving chemo- or radiotherapy used to be lowered, while PSP could restore the lowered immune functions and resist the virus invasion, thus reduce the secondary infection, facilitate rehabilitation and increase the survival rate. It is well known that 60% of the mortality in late stage of cancer is due to secondary infection. Statistics has been made for the survival rate in 100 cases of cancer patients by the Tumor Hospital affiliated to the Shanghai Medical University, the survival rate in PSP group is 72% while that of the control group is only 42%.

d. Alleviation of pain

The cancerous pain is a hardly endurable one. About 50% of cancer patients in moderate or advanced state complain of pain. The commonly used anticancer drugs such as Vinblastine, Cisplatin etc. can also induce neuralgia. PSP itself is not an analgesic drug. However, body-twisting test, hot plate test, electric stimulation test and acute and chronic inflammation pain tests, or phase II and phase III clinical trials all confirmed that PSP could alleviate pain to some extent.

e. Improvement of appetite in cancer patients

About 40-50% cancer patients complain of poor appetite. Medication with chemotherapeutic drugs induces loss of appetite even anorexia in about 80% of the late stage cancer patients. The TCM treatment of diseases is based upon stimulation of appetite. Stomach is like the sea for a valley which should not be weakened and evacuated, otherwise all kinds of evil forces will invade. Pharmacological and clinical studies have verified that PSP could antagonize the reduction of appetite, increase the dietary intake of the patients, thus supplement nourishment, strength the physical constitution and favor the increase of therapeutic efficacy.

 

f. Decrease of cancer risk

Cancer used to be identified abruptly but cancer is not a disease of sudden onset. The formation and development of malignant tumor require 20-30 years in gneral. Its sequence of transformation is shown as follows:-

Normal cells ® Precancerous cells ® Cancer cells ® Minute cancer ® Cancer in situs ® Infiltrative cancer

The reason why people are so fearful of cancer is that the disease used to be identified in its middle or late stages when the tumor is hardly curable. Prior to it there used to be no obvious clinical manifestation and minute cancer less than 2 mm in diameter is not easily identified by CT. Therefore, strategy to combat cancer has to be stressed on early precancerous stage.

The conventional pharmacological studies have demonstrated that PSP owns a protective action against the mutagenesis induced by carcinogenic agent-cyclophostamide, PSP could eliminate the damage of hepatic cells caused by carcinogenic compound-tetrachlorocarbon, PSP could activate the activity of anticancer immune cells, increase the production of anticancer immune factors, suppress the synthesis of DNA and RNA in the cancer cells, induce the malformation of the chromosome of the cancer cells, retard the mitotic cycle of cancer cells, stimulate the apoptosis of cancer cells. Therefore, "nimbleness and longevity following long term consumption of Yun Zhi" as state in TCM is justified.

PERSPECTIVE

With the effort made by all of us, PSP has won wonderful merits. PSP is the only state level superb drug of Yun Zhi and also is one of the two Yun Zhi anticancer products publicly acknowledged by the international academic community. Since the advances of scientific research is limitless, further studies are expected to be carried out.

1. The clinical indications for PSP approved by the Ministry of Public Health are confined to gastric, pulmonary and esophageal carcinomas. However, pharmacological study and part of the clinical trials have shown that PSP is also of help in the treatment of hepatic, intestinal, mammary, nasopharyngeal carcinomas, leukemia and melanocarinoma. Thus, more cancer patients could be favoured by PSP treatment.

2. Owing to the fact that PSK of the same category of BRM has already been applied in the treatment of chronic rheumatism, diabetes, nephritis and those immunity-related difficult diseases, attempt has to be made for PSP accordingly. It is known that PSP could activate phargocytosis of ovum of parasites, conducive to the prevention of growth for those intracellular parasites, such as taxoplasmosis. Colling, R.A. and Ng, T.B. have reported that PSP could block the combination of HIV virus with CD4+ cells and inhibit HIV reverse transcriptase and glycosylated enzymes at low dose level. It is expected that PSP could play a unique role in the comprehensive treatment of HIV disease.

3. It is known that Yun Zhi laccase is the best laccase from the fungi. Besides the wide application of laccase to speed up the drying of lacquer, it is also the key enzyme in the biosynthesis of the highly effective anticancer drug – Vinblastin. At present, Vinblastine is extracted from Catharanthus raseus with high cost and low yield. If laccase could be extracted from the fermentation fluid during the production of PSP to biosynthesize Vinblastine Vincristins for comprehensive utilization, better results are expected.

4. So far active components have been extracted from the traditional medicinal materials to reverse the cancer cell activity and thus established the mode. Similar PSP studies have also been started to compel the cancer cells "from the evil to the positive". This is our common goal.

In spite of the fact that cancer has not been wholly overcome yet, it is believed that mankind will eventually conquer the cancer demon. The traditional Chinese medicine will certainly contribute a striking merit in the struggle to overcome cancer!

In summary, clinical trials have proven that PSP is safe and effective as an adjuvant therapy in cancer patients, showing an overall effectiveness rate of 85.8%, while for patients in the control groups it was only 41.9%.

NOTE TO READER:

A report from the Suzhou Institute for Traditional Chinese Drugs suggests that larger doses of PSP at 5 grams (equivalent to 12 capsules of Yun Zhi) three times per day might be more effective than the routine doses used at present. Another individual trial on high dose therapy with PSP was done by B.Y. Li using a dose of 5.1 g three times a day. Since to date, no marked toxicity has been observed in any of the cases treated by these authors, it can be concluded that higher dosage would yield better results to the cancer patient.

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Ingredients:    100% essence of Yun-zhi mushroom