Tuesday, November 30, 2010

Utilizing Chinese Medicines to Improve Cancer Therapy - Fiction or Reality?

Despite the tremendous effort on research and development by government and industry, effective treatment of cancer in most patients remains elusive at present. Even if a given chemotherapeutic regimen is very effective at onset, it eventually will fail, due to drug resistance and /or organ toxicity. Thus, there is a great need to incorporate new mode of therapeutic approach in prevention and treatment of cancer. Chinese medicines (CM) have been used in China for about 5000 years for symptomatic treatment of diseases including cancer. The traditional approach of CM is to use different herbal formulae to restore the balance of Yin-Yang of body energy so body function can be normalized. Can this traditional Chinese medicine (TCM) approach provide an alternative to the evidence based conventional cancer chemotherapy? It would be a fiction to expect TCM to substitute as an alternative approach to modern cancer chemotherapy, despite its thousands of years of use in China. However, there are distinct potentials, from theory to herbal compounds, which could be derived from CM. For example, the balance concept of TCM may be an intriguing therapeutic approach for future cancer therapy— aiming not to eradicate all cancer cells but to keep it in balance with normal cells to result in bodily function as close to normal as possible and maintain in such a state as long as possible. Another potential contribution of TCM is its rich source of active anticancer compounds and their combinations which could be developed and proved to be effective therapeutic regimens (or adjunctive regimens) in the future. In tracing the source of new drugs for cancer, more than half of current anticancer agents used clinically in USA are either natural occurring or derived from natural products. These include Vinca alkaloids, taxanes, podophyllotoxin, camptothecins and anthracyclines. Despite the interest in plant-based new drug discovery, only a small portion of more than 250,000 known plant species have been investigated for cancer drug discovery. It is likely that herbs used in TCM can be a useful source of new anticancer drugs. Furthermore, the TCM formulae themselves (which always composed of mixtures of components) may simultaneously target multiple cancer-causing genes/pathways and thus achieve superior effect as compared to single agents aiming for a single molecular target. Nevertheless, before any TCM product can be accepted by the Western world as complementary and alternative medicine for cancer treatment/prevention, it is crucial to identify bioactive components, understand their pharmacological mechanisms, and achieve quality control of a given product along with demonstrating its clinical efficacy. In this issue of Current Drug Discovery Technologies, eight review articles highlighting in more detail some of these important points relating to development of CM as anti-cancer drugs. These articles describe the potential use of the balance concept, examples of CM-derived drugs that have been approved by US FDA and new technology (chemoinformatics) and targets (drug transporters and other molecular targets) as well as TCM products and formulations used for lung cancer. We hope that this special issue will provide a glimpse of examples and new technologies that can be applied toward improving the development of CM, potentially leading to new and effective anti-cancer agents in the future.

Tuesday, November 23, 2010

Lymphoma, Chemotherapy, & Antioxidants

Oxidative stress is defined as a type of physiological stress on the body caused by the damage done by free radicals inadequately neutralized by antioxidants. It has long been known that oxidative stress is an essential mechanism by which chemotherapy works to treat cancer. However, the question of whether this is always the case is seldom debated openly. Taking a deeper look into the research literature yields many examples where oxidative stress on cancer cells has been shown to be counterproductive. For example, a study using human Burkitt lymphoma cells found that oxidative stress actually interferes with the ability of the chemotherapy drugs doxorubicin, cisplatin, etoposide, and cytarabine to cause cancer cell death.
When oxidative stress levels are reduced in cancer cells, their growth is more easily controlled through a process called apoptosis. During apoptosis, cells are removed by the immune system before they lose their cell wall, thus avoiding an inflammatory response to the dying cells.
However, when oxidative stress levels go up, cancer cell death happens through a slower, messier, and less effective pathway called pyknosis or necrosis. Additionally, the ability of the body to “clean up” the resulting cellular debris from cancer cell death is also inhibited by oxidative stress. The body’s house-cleaning cells (called monocyte-derived macrophages) cannot function optimally under conditions of oxidative stress (i.e. low oxygen levels).
The authors of the above-mentioned study on Burkitt lymphoma cells and chemotherapy suggest that including antioxidants in the treatment protocol may enhance chemotherapy-induced apoptosis and phagocytosis. (Shacter, Williams et al. 2000) A second study, involving the chemotherapy drugs etoposide and calcimycin, confirms this finding: Human Burkitt’s lymphoma cells were unable to die quickly by apoptosis in the presence of oxidative stress and instead died using the slower and messier method of necrosis. In this study, it was found that oxidative stress inhibited apoptosis by depleting cells of their energy source, which is called adenosine triphosphate (ATP). (Lee and Shacter 1999)
Related to these observations about the relationship between cellular oxidative stress levels is the widely held view in medicine that the use of antioxidant dietary supplements diminishes chemotherapy’s effectiveness. However, when one looks more closely at the existing published science on how antioxidants and chemotherapy combine, the true answer is not so definitive. Many research studies, encompassing cell culture tests in the laboratory and also animal and some human studies, are coming to a conclusion often very different from the conventional perspective that chemotherapy and antioxidants should never be combined.
One example is a human study in which researchers discovered that higher levels of the antioxidant selenium in the blood of patients with aggressive B-cell non-Hodgkin’s lymphoma correlated with increased achievable doses of anthracycline based chemotherapy, better treatment response, achievement of long term remission, and longer overall survival. It is important to note that in this study, however, the level of selenium present in the blood of patients was from their diet; the study was not a test of supplemented selenium. (Last, Cornelius et al. 2003) As seen in this study, higher levels of natural antioxidants can help treatment outcomes.
On the other hand, the decreased levels of antioxidants (or oxidative stress) that are caused by many chemotherapy treatments correlates with increased side effects. In patients with Hodgkin’s lymphoma, chemotherapy with Adriamycin, bleomycin, vincristine, and dexamethasone significantly decreases antioxidant levels. (Kaya, Keskin et al. 2005) In children with acute lymphoblastic leukemia who received high-dose methotrexate, oxidative damage to proteins as well as other factors was related to toxic side effects. (Carmine, Evans et al. 1995)
Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams. In previous issues of Avenues, we have researched this subject thoroughly for prostate, breast, lung, colon, and ovarian cancers. In this article, we turn our focus to lymphoma, conducting a systematic search for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy, providing evidence that antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.
For this paper, we searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers. We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. used cancer cell cultures), used animals, or involved human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Click here for the rest of the article 

Tuesday, November 09, 2010

How Is This Cancer Different From All Other Cancers?

Alex Comments:  As genetic medicine begins to enter the clinic Western Medicine has come full circle to embrace a concept that is germane to Chinese Medicine which is to classify the patients unique pattern with a disease not only the disease itself.  On the genetic level disparate cancers may have the same genetic mutation.    

"I was just diagnosed with BRAF-mutated colon cancer." I've never heard anyone say that, but there's no reason I should not. Our knowledge of cancer genomics is increasingly enabling physicians to target therapies at the aberrant biochemistry that underlies individual tumors. This is truly taking personalized medicine 1 step further -- not only is therapy tailored to patients, it is also tailored to the unique deficits and/or vulnerabilities of each patient's tumor.
My thoughts along these lines were jump-started by a recent research study published in The New England Journal of Medicine.[1] The report focused on mutations in ARID1A, a gene that is often mutated in ovarian clear-cell carcinomas and in endometrioid carcinomas. Among 119 cases of clear-cell carcinoma, 46% demonstrated ARID1A mutations; 10 of 33 cases of endometrioid carcinoma (30%) also showed ARID1A mutations. By contrast, no ARID1A mutations were found in the 76 high-grade serous ovarian carcinomas examined.
Both clear-cell and endometrioid ovarian carcinomas are relatively insensitive to platinum/taxane chemotherapy, which is the treatment of choice for high-grade serous carcinomas. Could this be related to the ARID1A mutations? If yes, would ARID1A mutations found in other tumor types also be resistant to platinum/taxane chemotherapy?

Cracking the Code to "Beat" Cancer

A study published in The New England Journal of Medicine in August[2] described the effectiveness of PLX4032 in shrinking the tumors of 81% of metastatic melanoma patients with the BRAFV600E mutation. Of 32 patients studied, 2 had no sign of disease at the end of the trial and 24 had tumor shrinkage of 30% or more. Only 2 patients' tumors showed no regression at all.
When BRAF is mutated, the normal function of the B-raf protein is altered in ways that can lead to birth defects early in life or to cancer in adults. PLX4032 inhibits the mutated B-raf protein regardless of the cell type in which it resides, but only in tissues with the BRAF mutation.
Considering the striking impact of PLX4032 on malignant melanomas, and its focused action against the aberrant B-raf protein, would PLX4032 also be active against other tumors with this same BRAF mutation?
According to the database of the Cancer Genome Project of the Wellcome Trust Sanger Institute, BRAF is mutated in 45% of thyroid cancers.[3] Not surprisingly then, a paper presented at the 2009 Annual Meeting of the American Society of Clinical Oncology[4] showed that PLX4032 is active in thyroid cancers as well: tumor regression rates were 9%-16% in thyroid cancer patients with BRAFV600E mutations, and patients showed no tumor progression for 4-7 months.
A 2008 study reported that inhibition of BRAF caused apoptosis in melanoma cells, but only arrested growth in thyroid carcinoma cells, with little or no cell death -- which might explain why although PLX4032 is clearly active in thyroid cancer, it has such different effects in melanoma than it does in thyroid cancer.[5]

A Rose By Any Other Name...

So how might our understanding of tumor classification change as genomic medicine moves into the clinic? In tissues such as thyroid, which is unique in its affinity for iodine, or in breast cancers requiring estrogen to thrive, these characteristics should obviously be exploited in ways that achieve apoptosis or growth inhibition. But it might be equally important to exploit the ways in which other tumors -- which might be dissimilar at first glance -- are actually similar on a genetic level. Just as PLX4032 seems to be active in a variety of BRAF-mutated tumors, other chemotherapeutic agents can be designed to target tumors with common genetic variants. Or, conversely, just as clear-cell ovarian cancers with ARID1A mutations are unresponsive to platinum/taxane chemotherapy, we might be able to avoid the use of these chemotherapies in other tumor types with the same mutation.
The more we learn about cancer genomes, the more we're beginning to understand that "BRAF-mutant colon cancer" should be treated differently from BRAF-normal colon cancer. Whether we'll ultimately be able to unravel every genetic mutation in every tumor type remains to be seen. But, in the meantime, investigations into treatments tailored toward a range of tumor types with ARID1A and BRAFV600E mutations clearly provide a window into the future of clinical oncology.

Thursday, November 04, 2010

Clinical Implications of Tai Chi Interventions: A Review: Abstract and Introduction

Michael Sieverts
Alex Comments:  If you are local to Los Angeles,  There is a wonderful Qi Gong class for cancer patients offered through the wellness community at Clover park in Santa Monica.  They teach a Qi Gong form called Guo Lin Qi Gong.  This form has a very interesting history.  This class is not just a form of exercise for cancer patients.  There are other aspects of the class that are not easily quantifiable. For example, it is powerful to get a group of people together who are all taking personal responsibility for their health sharing about it.  This aspect of the class the wonderful teacher Michael Sieverts calls, "Social Oncology". After the Qi Gong is taught some of the class then does a Tai Qi form which I have shown in a video below.   Tai Qi is one of the forms of Qi Gong in the same way that hatha yoga is one form of the bigger umbrella of all the yogic disciplines. 

The review of Tai Qi studies below is in part a way to quantify a feeling.  This is difficult to do.  To feel good from practicing is the key.  I hope to see you in the park. 

Tai Chi, a Chinese bodymind exercise, has been used in China for thousands of years for both prevention and therapeutic purposes. In the 1990s, the Western research community started to examine the effectiveness of Tai Chi interventions using scientific research design and standardized outcome measures. A number of reviews of these studies have been published. Based on an extensive literature search, this state-of-the-art review identified 25 such reviews published since 2000, provides a description of them, and summarizes what was learned from these reviews. Although there is still a need to understand more about Tai Chi interventions, especially Tai Chi's mechanism, it is concluded that Tai Chi is a very useful exercise format that can be used for a variety of chronic disease conditions. It requires no equipment and little space, and it can be practiced anytime, anywhere, and by older adults and individuals with chronic diseases. Since short forms (eg, 10 or 24 forms) have been shown to have similar benefits as longer ones, beginners should start using simple, short forms first. Like other exercise interventions, regular practice is a must to be able to gain maximal benefits. Tai Chi can be used safely as a complementary addition to conventional medical treatment, physical therapy, and rehabilitation, as well as with other exercise interventions.

For the entire Review click here



Monday, November 01, 2010

New Yorker Magazine Book Review: Cancer World The making of a modern disease

Alex Comments:  Interesting Book Review.

The risk-factor world holds out hope for avoiding cancer while recruiting masses of us into the anxious state of the “precancerous.” The physician and historian Robert Aronowitz offers an acute illustration of the problem: a fifty-eight-year-old woman diagnosed with breast cancer has a lumpectomy, followed by local radiation and months of chemo. After that, she is put on the anti-estrogen Tamoxifen for five years. As she finishes that course of treatment, she weighs the decision whether to go on a different type of hormonal therapy and what type and frequency of M.R.I. or mammogram to get. She is an active member of a breast-cancer-survivor group, and she closely monitors the latest developments on the Web. Meanwhile, another woman, the same age, has not received a breast-cancer diagnosis. She has, however, taken supplementary estrogen pills for several years in connection with menopause, and her doctor now tells her to stop, because estrogen may constitute a risk factor for breast cancer. She has been getting annual mammograms since she was forty, and four years ago an abnormal mammogram was the occasion for an aspiration biopsy. This proved negative, but her anxiety increases. She surfs the Web for information about risk factors, and she is struck by direct advertisements for Tamoxifen to prevent the development of breast cancer, for which she now believes she is at serious risk. The first woman had cancer; the second woman does not have cancer. But their experiences eerily resemble each other.

Read more http://www.newyorker.com/arts/critics/books/2010/11/08/101108crbo_books_shapin?currentPage=all#ixzz142wUXaq8