7 Feb 2013


The following was published yesterday on Gregory Pawelski's website CancerFocus.org :
What is chemoprevention and when is it used to prevent cancer?

Yuesheng Zhang, M.D., Ph.D.
Professor of Oncology
Roswell Park Cancer Institute

Cancer chemoprevention is defined as interventions with pharmaceuticals, vitamins, minerals, biologics, or other substances to retard, block or reverse the carcinogenic process. I would add that cancer chemoprevention is also important for inhibition of cancer recurrence. Hence, cancer chemoprevention is about preemptive strike against cancer. Before I go further, however, let me say a few words about carcinogenesis. Carcinogenesis is the developmental and also the silent process from normal cells to cancer cells, caused by chemicals, radiation or biological agents, and driven by genetic changes including activation of oncogenes (e.g. Ras) and inactivation of tumor suppressor genes (e.g. p53) as well as epigenetic changes. So, chemoprevention may be viewed as chemotherapy of carcinogenesis or chemotherapy of cancer recurrence.

Chemopreventive agents may be used in people at high risk of developing cancer and cancer recurrence. To date, the US Food and Drug Administration (FDA) has approved the following agents for cancer prevention: tamoxifen and rolaxifene against breast cancer, celecoxib against adenomatous colorectal polyps, fluorouracil against actinic keratosis, BCG (Bacillus Calmette-Guerin) against bladder cancer recurrence, HPV (human papilloma virus) vaccine against cervical cancer, and PDT (photodynamic therapy) with photofrin against Barrett Esophagus.

Is chemoprevention common? The answer is yes or no. If one looks at the drugs listed above, it is not that many. But if one includes dietary modification (e.g. eating more vegetables and less oily foods), which certainly modifies cancer risk, then chemoprevention is very common. Everyone should be doing it. In fact, dietary modification may have the greatest impact on reducing cancer risk among all chemopreventive approaches.

When we talk about cancer chemoprevention or cancer prevention, it is important to recognize the concept of cancer prevention by delay. Whatever we may be doing, we may not totally stop cancer, but if prevention can delay cancer occurrence/diagnosis by 10 years or so, cancer incidence will be dramatically reduced, because many people will die with cancer but not of cancer.

The list of cancer chemopreventive targets is long; basically, any genes, proteins or biological agents that play important roles in carcinogenesis and cancer progression may be potential chemopreventive targets, as long as they are druggable. Indeed, numerous genes and proteins have been studied as chemopreventive targets. Targets of chemopreventive agents approved by the FDA include: Estrogen receptor, targeted by tamoxifen and raloxifene for breast cancer prevention; cyclooxegenase-2, targeted by celecoxib for prevention of colon cancer; human papilloma virus, targeted by HPV vaccine for prevention of cervical cancer; thymidylate synthase, targeted by fluorouracil for skin cancer prevention. Finasteride, which targets 5-alpha reductase, has shown clinical efficacy in prostate cancer prevention, but has not been approved by the FDA.

I should also mention that some of the FDA-approved cancer chemopreventive agents do not have clear targets, e.g. BCG for prevention of bladder cancer recurrence, and PDT with phtofrin for prevention of esophageal cancer.

It is not possible to name a single best cancer prevention diet as far as specific foods are concerned. But it has been widely recognized that a diet with an emphasis on plant foods (fresh vegetables and fruits) which also maintains a healthy body weight prevents cancer and other diseases. This is supported by numerous scientific studies; just to mention a few below. We know that vegetables and fruits contain chemicals that fight cancer (e.g. sulforaphane in broccoli, resveratrol in grape), whereas carcinogens (e.g. heterocyclic amines and polycyclic aromatic hydrocarbons) are formed in meat cooked in high heat (e.g. grill). Alcohol is also potentially carcinogenic, so drinking in moderation or no drinking is recommended. We also know that overweight and obese are causatively linked to many forms of cancer.

There is very strong and ever accumulating evidence about cruciferous vegetables reducing risk of most if not all cancers. The International Agency for Research on Cancer, World Health Organization, devoted one volume of the IARC handbooks of cancer prevention to this subject: Volume 8, entitled “Fruit and Vegetable” (IARC Press, Lyon, 2003, ISBN 92 832 3008 6), which provided a comprehensive account of the cancer protective activities of fruits and vegetables. Cruciferous vegetables are full of phytochemicals that have been repeatedly shown to fight cancer in preclinical studies and epidemiological studies. We have certainly seen the cancer preventive activities of cruciferous vegetables in our own studies of bladder cancer.We showed that mustard seed powder and its active ingredient allylisothiocyanate, when fed to rats, both inhibited bladder cancer growth and muscle invasion (see papers mentioned in Answer 2), that sulforaphane, which is abundant in broccoli, inhibited tobacco carcinogen-induced DNA damage in the bladder in mice (Ding et al., Carcinogenesis 31, 1999-2003, 2010), that broccoli sprout extracts inhibited bladder cancer development in rats (Munday et al., Cancer Research, 68, 1593-1600, 2008), and that cruciferous vegetables intake, especially broccoli, was inversely associated with bladder cancer risk and positively associated with bladder cancer survival in human (Tang et al., Cancer Epidemiology, Biomarkers & Prevention, 17, 948-944, 2008; 19, 1806-1811, 2010).

A very large number of phytochemicals from cruciferous vegetables have been shown to modulate various steps and processes involved in cancer development and progression. This includes but not limited to scavenging of reactive oxygen species, inhibition of cellular enzymes that activate carcinogens, induction of carcinogen-detoxifying enzymes, induction of antioxidant enzymes, modulation of cell cycle progression, activation of programed cell death and inhibition of angiogenesis. Two review articles I published a few years back on two cruciferous vegetable phytochemicals provide additional useful information: Zhang and Tang, Discovery and development of sulforaphane as a cancer chemopreventive phytochemical, Act Pharmacol Sin 28, 1343-1354, 2007; Zhang, Allylisothiocyanate as a cancer chemopreventive phytochemical, MolNutr Food Res 54, 127-135, 2010. Cruciferous vegetables also contain vitamins, minerals and other nutrients. There are also studies showing inverse association between dietary fiber intake and cancer risk in the colon, breast and prostate.

While many Chinese herbs and their active ingredients have been shown to possess cancer preventive activities, lack of standardization and quality control have slowed the progress. My own research experience tells me that the level of an active ingredient in a given plant can vary dramatically depending where and when the plant is grown, how the plant is harvested, processed and stored, how long the plant has been stored, and things of that nature. Just to give you an example about what I am talking about, at one point we were interested in horseradish powder for cancer prevention, and bought the powder from a company on two occasions. It was the same catalog number and the same name, and the company swore that the two powders were exactly the same, but upon lab analysis we found that the level of the active ingredient (allylisothiocyanate) in the two powders differed by more than 50 fold.
By David S. Alberts, M.D.
Director, Arizona Cancer Center
University of Arizona

There may be a role for chemoprevention in lowering the risk of ovarian cancer and ovarian cancer recurrence. Dr. Alberts points out that there is an especially strong rationale for chemoprevention in ovarian cancer.

The overall five-year survival rate for ovarian cancer is about 31% (according to National Cancer Institute figures), and more than 70% of women in remission on primary chemotherapy will experience disease recurrence and ultimately die.

Diet and physical activity remain potential modifiable risk factors for this disease. Alberts points out that data from the large Women's Health Initiative study suggested that a low-fat eating plan is associated with a reduced risk for ovarian cancer.

In addition, data show that a high milk intake may be a possible harmful prognostic factor for ovarian cancer, while data from the Iowa Women's Health Study indicated that a high intake of vegetables improved ovarian cancer survival.

Additionally, data from the Women's Healthy Eating and Living (WHEL) Study showed that women who followed both diet and exercise recommendations had lower recurrence rates and better survival rates.

There are specific mechanisms by which physical activity may serve to lower the risk of ovarian cancer. Physical activity can:

* improve immune functioning

* reduce ovarian oestrogen production

* reduce body fat (thereby reducing fat-produced oestrogens and the potential for storage of fat-soluble carcinogens)

* increase sex-hormone binding globulins

* reduce circulating insulin and glucose

* reduce the activity of COX-2 and levels of prostaglandins in ovarian epithelium.

Dr. Alberts will serve as the study chair for the GOG-225 Diet and Exercise Trial: "Can diet and physical activity modulate ovarian cancer progression-free survival?"

The enrollment target is 1,070 women, and the primary objective is to determine if disease-free women who have completed therapy for Stage II-IV ovarian, fallopian tube, or primary peritoneal cancer randomized to a healthy lifestyle intervention have increased progression-free survival compared with those randomized to usual care.

Secondary objectives are to determine whether women in the intervention group have improved general quality of life and improved physical functioning. The protocol revisions are under review for GOG-225, funding is in place for start-up, and activation is planned for January 2012.

Source: Oncology Times
Gregory D. Pawelski

1 comment:

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