Chemoprevention, Naturally: Findings On Plant-derived Cancer Medicines

That is, according to research presented December 6, at the American Association for Cancer Research's Sixth Annual International Conference on Frontiers in Cancer Prevention Research, being held in Philadelphia, Pennsylvania.

Topically applied black raspberry gel applied on oral premalignant tumors

Oral squamous cell carcinoma is a deadly cancer that, even when treated successfully, often leaves patients permanently disfigured. Other than radical surgery, there are few known treatments. Researchers at Ohio State University, however, report a Phase I/II trial demonstrating that a gel made from black raspberries shows promise in preventing or slowing the malignant transformation of precancerous oral lesions.

"Black raspberries are full of anthocyanins, potent antioxidants that give the berries their rich, dark color, and our findings show these compounds have a role in silencing cancerous cells," said Susan Mallery, D.D.S., Ph.D., professor in the Department of Oral Maxillofacial Surgery and Pathology at Ohio State University's College of Dentistry. "This gel appears to be a valid means of delivering anthocyanins and other cancer-preventing compounds directly to precancerous cells, since it slowed or reduced lesion progression in about two-thirds of study participants."

According to American Cancer Society statistics, oral cancer is one of the deadliest of all cancers, with about 35,000 new cases each year in the United States and 7,500 deaths annually. These cancers generally begin as small, often unnoticed, lesions inside the mouth. "More than a third of untreated precancerous oral lesions will undergo malignant transformation into squamous cell cancer, but we do not have the capability to predict which lesions will progress," Mallery said.

The National Cancer Institute-funded trial included 30 participants, 20 of whom had identifiable precancerous lesions, and 10 normal controls. Each of the participants was instructed to gently dry the lesion sites (or a pre-selected control site for the normal participants) and rub the gel into the area four times a day, once after each meal and at bedtime.

After six weeks, about 35 percent of the trial participants' lesions showed an improvement in their microscopic diagnosis, while another 45 percent showed that their lesions had stabilized. About 20 percent showed an increase in their lesional microscopic diagnoses. Importantly, none of the participants experienced any side effects from the gel.

"The trial was designed to test the safety of the gel and detect any possible toxicity, but the next obvious step is a multicenter, double-blind, placebo-controlled Phase II study," Mallery said. "Such a study would enable us to determine that the black raspberries are the active factor and not just the gel base or the act of drying and rubbing the lesions."

The researchers also collected cell samples from the lesion sites of each participant before and after treatment in order to study the genetics and biology of the lesions. The majority of patients with precancerous lesions at the start of the trial showed elevated levels of COX-2 and iNOS, two proteins closely correlated with inflammation and malignant progression. Following treatment, Mallery says, levels of those proteins in the treated lesional epithelial cells decreased dramatically.

Mallery and her colleagues also examined samples for three tumor suppressor genes in order to determine what researchers call "loss of heterozygosity," whether or not a cancer cell has lost one of its two copies of the gene. Such loss greatly increases a cell's chances of losing the benefit of the tumor suppressor genes due to a second mutation or gene silencing event. Following the trial, the researchers noted that many lesions returned to normal, retaining both copies of each tumor suppressor gene. "We speculate that the chemopreventive compounds in black raspberries assist in modulating cell growth by promoting programmed cell death or terminal differentiation, two mechanisms that help "reeducate" precancerous cells," Mallery said.

"Oral cancer is a debilitating disease and there is a desperate need for early detection and management of precancerous lesions," Mallery said. "While screening can help detect the disease early -- and survival rates are definitely improved the earlier the disease is caught -- many of these precancerous lesions recur despite complete surgical removal. There are currently no effective chemopreventive treatments which could conceivably serve as either adjunctive or alternative approaches to surgery."

According to Mallery, the development of black raspberries as potential cancer-fighters is the result of decades of research into identification of naturally derived chemopreventive compounds by Ohio State researcher Gary D. Stoner, Ph.D., an emeritus professor at Ohio State University's College of Medicine and Public Health. Clinical studies stemming from his research are currently underway for oral, esophageal and colorectal cancer.

The gel looks deceptively like black raspberry jam, but it certainly does not taste like something you would want to spread on toast, Mallery says. The bioadhesive gel, which contains 10 percent freeze dried black raspberries, is devoid of many of the tasty sugars found in native berries.

The black raspberry gel was manufactured by the University of Kentucky's Good Manufacturing Production (GMP) facility. NanoMed Pharmaceuticals is partnering with OSU investigators Mallery, Stoner and Peter E. Larsen D.D.S. and Russell J. Mumper, Ph.D., of the University of North Carolina, in product development.

Suppressive effects of a phytochemical cocktail on prostate cancer growth in vitro and in vivo

A commercially available nutrition drink reduces the growth of tumors in a mouse model of human prostate cancer by 25 percent in two weeks, according to researchers from the University of Sydney. The drink, Blueberry Punch, is a mixture of plant-based chemicals -- phytochemicals -- known to have anti-cancer properties.

In particular, Blueberry Punch consists of a combination of fruit concentrates (blueberry, red grape, raspberry and elderberry), grape seed and skin extract, citrus skin extracts, green tea extract (EGCG), olive leaf and olive pulp extracts, tarragon, turmeric and ginger.

"We have undertaken efficacy studies on individual components of Blueberry Punch, such as curcumin, resveratrol and EGCG, in the same laboratory setting and found these effective in suppressing cell growth in culture," said Jas Singh, Ph.D., research fellow at the University of Sydney.

"While individual phytochemicals are successful in killing cancer cells, we reasoned that synergistic or additive effects are likely to be achieved when they are combined."

Singh and her colleagues studied the effect of the beverage on both cancer cell cultures and in mouse models that mimic human prostate cancer. After 72 hours of exposure to increasing concentrations of Blueberry Punch, prostate cancer cells showed a dose-dependent reduction in size and viability when compared with untreated cells, Singh says. After feeding mice a 10 percent solution of the punch for two weeks, the tumors in the test mice were 25 percent smaller than those found in mice that drank only tap water.

Because Blueberry Punch is a combination of several ingredients, it could have multiple mechanisms of action, Singh says. "Based on our initial findings, the mechanisms include, at least, the inhibition of the inflammation-related pathways, which is similar to the action of non-steroidal anti-inflammatory drugs; and inhibition of cyclin D1, which is similar to green tea action."

Based on these results, the researchers believe Blueberry Punch is now ready for human prostate cancer trials. Because Blueberry Punch is a food product rather than a drug, it is unlikely to have adverse reactions or side effects assuming that the individual is tolerant to all ingredients, Singh says. "The evidence we have provided suggests that this product could be therapeutic, although it requires clinical validation," Singh said.

The study was partially funded by the makers of Blueberry Punch, Dr. Red Nutraceuticals, a firm located near Brisbane, Australia, but the experiments were designed and conducted independently in the University of Sydney.

Inhibition of colorectal tumorigenesis in azoxymethane (AOM)-treated rats by green tea polyphenols

Elucidating a decade's worth of conflicting studies of the cancer-fighting benefits of green tea, researchers at Rutgers University have conclusively demonstrated that a standardized green tea polyphenol preparation can prevent the growth of colorectal tumors in a rat model of human colorectal cancer.

Results from previous studies using different tea constituents in this particular rat cancer model, which is thought to closely mimic human cancer, had been inconsistent. The researchers believe their findings will pave the way for clinical trials with green tea polyphenols in humans.

"Our findings show that rats fed a diet containing Polyphenon E, a standardized green tea polyphenol preparation, are less than half as likely to develop colon cancer," said Hang Xiao, Ph.D., research associate at the Department of Chemical Biology in Ernest Mario School of Pharmacy of Rutgers University.

According to Xiao, these results are consistent with previously published results by the project's primary investigator, C.S. Yang, Ph.D., professor and chair of the Department of Chemical Biology at Rutgers, which showed that green tea consumption was associated with lower colon cancer rates in Shanghai, China.

Xiao and his colleagues treated two groups of mice with azoxymethane (AOM), a widely used agent that has been shown to generate in rats colorectal tumors that share many characteristics with colorectal cancer in humans, Xiao says. They then split the rats into two groups that were each fed a high fat diet, which the researchers believe closely resembles a Western diet; half received a 0.24 percent solution of Polyphenon E. According to Xiao, the green tea extract contains four major polyphenols, the majority of which (about 65 percent) is EGCG, thought to be the main active ingredient.

"When you account for caloric consumption, 0.24 percent Polyphenon E in diet gave the experimental rats the equivalent of about four to six cups of tea a day," Xiao said. "While I can't make any recommendations for how much green tea people should drink each day, it isn't uncommon for some to drink that much tea."

After 34 weeks, rats that received Polyphenon E developed 55 percent fewer tumors compared to the control rats that did not receive Polyphenon E. Moreover, the tumors were 45 percent smaller in rats treated with green tea extract. Histopathological analysis by his colleague, Xinpei Hao, Ph.D., also showed that the treatment group had significantly lower incidence and number of malignant colon tumors. The researchers could also detect green tea polyphenols in the blood plasma as well as the colorectal mucosa of the rats who received the extract.

Meanwhile, the test rats weighed about five percent less than their control group counterparts, a result Xiao attributes to the ability of the green tea polyphenols to block lipid absorption in the body, which the researchers had previously demonstrated in a mouse model of obesity.