Current Issue	Past Issues	About YSM	Subscriptions	Advertisements	Contact Us

79.4 - Summer 2006

From the editor Articles News Features Departmental notes In Memoriam Undergrad profile Book reviews Opinions 25, 50, 100 years ago Puzzle corner

Search YSM Articles

Advanced Search

> Summer 2006 > Articles

By Qing Wang

For the stressed-out, sleep-deprived college student, catching a cold during exam periods can prove disastrous. Many students of Chinese heritage, however, are well-equipped with the thousand-year-old remedy, banlangen (Radix isatidis), an herb used extensively in traditional Chinese medicine (TCM) to treat respiratory diseases, such as the cold and flu. During the SARS outbreak, demand for banlangen skyrocketed, often exceeding the available supply.

Why is traditional Chinese medicine still so popular in an age of biochemistry, molecular biology, and Western medicine? "There are unmet clinical needs and unfulfilled scientific hopes," explains Yung-Chi Cheng, Henry Bronson Professor of Pharmacology.

Each year, for example, the common cold afflicts the average adult two to four times and children up to twelve times. Conventional Western medicine, however, offers no cure at present. This same unmet clinical need has led numerous cancer patients to turn to alternative medical systems such as TCM to complement their "conventional" treatments.

Unlike many other traditional medical systems, TCM has not become extinct after the rise of modern Western medicine; in fact, it remains an integral part of the public health care system in China. Chinese medical practice finds its roots in two concepts of ancient Chinese philosophy: yin and yang and the five cyclically related elements of nature (wood, fire, earth, metal, and water).

In Chinese philosophy and science, the opposing forces of yin and yang operate as a dynamic system for classifying objects, processes, and forces in nature. As it applies to pathology, yinyang theory describes patterns of change. For example, when yin is too strong, yang is diseased and vice versa. Therefore Chinese medicine uses highly individualized treatment to restore the balance between yin and yang.

In Hippocratic medicine, diseases are also described as imbalances in the forces of the body; thus, Western medicine in its earliest form actually resembled Chinese medicine in many ways. The rise of anatomical studies at the organ, tissue, and cellular levels, however, marked a dramatic paradigm shift in Western medical thinking from a holistic point of view to a reductionist one.

With a new array of technologically advanced tools, scientists today are exploring the human body at even the molecular level. Needless to say, reductionism has catalyzed the development of effective medical treatments that have led to drastic improvements in lifespan and quality of life.

Trained as a conventional cancer and viral pharmacologist, Cheng has become the leading expert on biochemical and molecular pharmacology. Yet seven years ago, he also began to explore TCM for widespread clinical use. Given the success of the Western approach and his research in this field, why explore Chinese medicine?

Western medicine typically uses isolated compounds to treat a single physiological target; however, cancer, like diabetes, arthritis, neurodegenerative diseases, and other disorders associated with aging, is a multifactorial disease with a complicated etiology. In the development of cancer treatments, the reductionist approach can make only incremental contributions to understanding the disease and benefit only a small part of the patient population.

Thus, in order to help the majority of patients, future treatments will need to use individualized polychemical regimens that target not only a single pathway or disease tissue but also the entire system. Moreover, unfilled medical needs are making medical scientists recognize that individualized medicine may become a standard for treating patients in the future.

But Chinese physicians have been following this standard for thousands of years. Chinese herbal medicine, one of eight techniques used in TCM treatments, uses polychemical formulations that are prescribed on an individual basis and emphasizes the dynamic balance between different parts of the body as well as the interactions between the different herbs within a formulation. Moreover, TCM as we know it today is based upon over four thousand years of empirical knowledge accumulated through direct testing in humans, not model animals.

So why not learn from history? "Human nature is often too egotistical, and we forget about our history," states Cheng. "It’s time for West to meet East."

Banlangen is taken by many Chinese college students heritage to prevent cold and flu. Pharmacological studies suggest that it has antibiotic effects in vitro, and its immunostimulant and antiplatelet effects have been shown in animal models.

Although the general public in the Western world has been eager to embrace TCM as a complement to their disease treatments, especially in cases of cancer and chronic diseases, the scientific and medical communities have been far less receptive.

A major source of the distrust that Western practitioners have towards TCM is its dependence on anecdotal and experience-based knowledge rather than on clinical or scientific evidence derived through systematic experimentation. Thus, Cheng’s goal is to transform experience-based TCM to evidence-based medicine that can be accepted more easily by the rest of the world.

That is not to say that there have been no past attempts to analyze TCM therapies using Western techniques. Such studies, however, often removed the therapeutic techniques from their context. Studies on herbal medicine, for example, separated herbal formulations into their chemical components and tested each fraction individually. Many formulations, however, appeared to lose their potency when dissected in such a manner.

The herbs in a typical TCM formulation, Cheng explains, play different roles. Jun, the emperor herb, is the principle ingredient; chen, the minister herb, aids the jun often by augmenting or broadening its effects or by attending to secondary symptoms; zuo, the assistant, can moderate the activities of the jun and chen or also address secondary symptoms; finally, shi, the ambassador herb, aids in the absorption and transport of the all the other herbs to their destinations. Thus, the herbs prescribed in a given formulation must work in concert to achieve a desired effect.

Colorectal cancer is the second deadliest cancer in the US. Although treatment is available, irinotecan (CPT-11), the main drug used for colon cancer, decreases white blood cell count and damages gut mucosal epithelium, leading to severe diarrhea, dehydration, and sometimes even death.

Hoping to improve the quality of life of patients undergoing chemotherapy for colon cancer, Cheng searched through TCM literature for relevant treatments.

Chinese herbal medicine can be used for cancer treatment in three different ways: as an adjunct to chemotherapy for enhancing effectiveness or moderating side effects, directly as chemo- or biotherapy, or as preventive therapy. Cheng found a four-herb formulation, PHY906, which has been used for over 1800 years to treat gastrointestinal complaints, including those that are general side effects for chemotherapy.

In 1998, Cheng founded the New Haven-based biotech company, PhytoCeutica, to develop TCM therapies such as PHY906 into FDA-approved cancer drugs by conducting both preclinical and clinical studies.

First, Cheng needed to ensure that it would not undermine the effectiveness of chemotherapy. Using a mouse model system, Cheng tested PHY906’s effects on chemotherapy treatments for colon, liver, and pancreatic cancers with different mechanisms of action. In all conditions, PHY906 not only did not compromise the chemotherapy but actually enhanced its effectiveness.

Cheng is also collaborating with other researchers in studying herbal formulations as well as nutrition foods and their effects on cancer. Zhinan Yin, assistant professor of rheumatology, is studying AHCC (active hexose correlated compound), a four-mushroom mix that is marketed as a nutritional supplement in Japan.

Through animal studies, Yin observed that AHCC increases the number of gamma, delta, and CD8 T cells and reduces tumor tissue. Thus, AHCC enhances tumor surveillance through both the innate and adaptive immune response.

Professor Zhinan Yin observed that administering AHCC (active hexose correlated compound), a nutritional supplement marketed in Japan, resulted in reduced tumor size in mouse intestine, as shown by the graph and picture above.

Herb quality can vary considerably depending on place and season of cultivation. To move PHY906 into clinical trials, many more quality control measures are necessary. Within the past decade, Cheng has played a critical role in convincing the FDA to adopt a different view on testing and approving TCM herbal therapies for clinical use. In the new approach, an approved formulation must fulfill three criteria: satisfy unmet clinical need, pass tests for efficacy and toxicity, and meet standards of consistent preparation.

Quality control of complex mixtures, however, has posed a considerable scientific challenge. What parameter does one measure? How does one then measure and compare it between samples? Traditional quality control monitors few compounds as chemical markers and single enzyme or receptor readouts as biological markers. For a complex mixture, however, a much higher number of parameters must be monitored.

With PhytoCeutica, Cheng developed a technology platform, PhytomicsQCTM, for monitoring the consistency of herbal formulations through both chemical and biological fingerprinting.

Using liquid chromatography and mass spectroscopy, PhytomicsQC can identify over a hundred different masses in the mixture and assign tentative structures to eight percent of them. To profile mixtures through the biological responses they induce, PhytomicsQC uses cells as sensors, DNA as response elements, and RNA as the readout to obtain a gene expression fingerprint.

Having developed a dependable quality control method, Cheng identified an experienced pharmeutical company in Taiwan to make the preparations for his clinical studies using the FDA-approved Good Manufacturing Practice (GMP).

Preps made under GMP shared over ninety-five percent similarity based on PhytomicsQC’s comparison index. As a comparison, preps obtained from other sources were less than seventy percent similar.

With the quality control issue resolved, PhytoCeutica then conducted clinical trials of PHY906 at five sites throughout the country. Edward Chu, chief of medical oncology and director of clinical research at the Yale Cancer Center, oversaw the Phase I study at the Yale VA.

In these trials, colorectal cancer patients were treated with a standard regimen of irinotecan, fluorouracil, and leucovorin. Serving as their own controls, patients were also given PHY906 during one half of their treatment and placebo during the other.

The study clearly showed that PHY906 reduced the need for antidiarrheal medicine and the frequency of vomiting or diarrhea during therapy. Chu’s team has already begun a follow-up phase II study for PHY906 in colorectal cancer therapy, as well as phase I studies for use with liver cancer and pancreatic cancer therapies.

So why did PHY906 work? Cheng postulates that the herbs were able to target cells resistant to chemotherapy, perhaps by inhibiting multi-drug resistance proteins or by facilitating oral uptake and drug delivery. Cheng is conducting experiments to continue testing PHY906’s mode of action.

Once driven primarily by popular demand, integrative medicine—combining conventional treatment with alternative medicine like TCM—has caught the attention of medical researchers. Integrative medicine not only calls upon conventional health care methods but also emphasizes preventative medicine that often relates to lifestyle management (diet, exercise, stress, and emotional management).

In this way, "Western medicine" is becoming more and more similar to "Eastern medicine." In a parallel movement, basic science research is moving progressively towards integrating the information we have amassed at the molecular and cellular levels of individual parts of biological systems.

This new "systems biology" focuses on identifying relationships and interactions within the body. Sound familiar? As Cheng likes to say, we can reinvent medicine by rediscovering history.

Science Links

Present your research to New Haven high school students (Synergy Outreach) Astronomy Picture of the Day (NASA) BBC Science & Nature (BBC) Learn how our lifestyles can change the way our genes work, examine a yet-to-be-broken code on a sculpture called Kryptos, see preserved dinosaur blood vessels (NOVA ScienceNow) Watch Health Videos: Weight-loss surgery to caffeine on the brain (CNN Health News) Science, Health, Environment & Technology (ScienceDaily)

Copyright 2013 Yale Scientific Publications, Inc. - Disclaimer