Licorice and cancer.

Licorice root is one of the oldest and most frequently employed botanicals in Chinese medicine. In the United States, licorice products are most often used as flavoring and sweetening agents in food products. Constituents of licorice include triterpenoids, such as glycyrrhizin and its aglycone glycyrrhizic acid, various polyphenols, and polysaccharides. A number of pharmaceutical effects of licorice are known or suspected (anti-inflammatory, antivirus, antiulcer, anticarcinogenesis, and others). Licorice and its derivatives may protect against carcinogen-induced DNA damage and may be suppressive agents as well. Glycyrrhizic acid is an inhibitor of lipoxygenase and cyclooxygenase, inhibits protein kinase C, and downregulates the epidermal growth factor receptor. Licorice polyphenols induce apoptosis in cancer cells. These and other activities of licorice are reviewed, and a rationale is suggested for combinations of agents in preventive clinical trials.

Results of a volunteer program to conduct dietary intervention research for women.

The American Cancer Society (ACS) initiated the Breast Cancer Dietary Intervention Project (BCDIP) to involve community volunteers in cancer-related intervention research activities focused on dietary fat reduction in women with breast cancer. This article presents data on the volunteer aspects of the project, with two aims: (a) to describe the volunteer recruitment and intervention designed for the BCDIP, conducted jointly by the American Cancer Society and the Fred Hutchinson Cancer Research Center, and (b) to present baseline characteristics and predictors of retention of the BCDIP volunteers. There were five types of volunteers, called volunteer adjunct researchers or VARs, in the BCDIP. VARs were recruited using a variety of approaches, including electronic media alerts, flyers in oncology clinics, and notices in the newsletters of state nursing and nutritional professional organizations. Over half of all VARs came from two main sources: the media (television, radio, newspapers) and from work-related sources. Over half (58%) of the VARs had professional licenses in nursing or dietetics, and 46% were employed full-time. Several types of motivations for participating in the BCDIP, including altruistic reasons (want to help others, help people with cancer), health concerns (family/friend with breast cancer, have had cancer), and work-related reasons (gain professional skills) were important. Sixty-eight percent of VARs remained with the project for its entirety. Predictors of retention in the VAR program included previous ACS volunteer experience with initial motivations to volunteer and the interaction of employment status and professional nursing training. In future research and community-based projects, better recruitment and volunteer coordination procedures should be used to reduce dropout rates and maintain volunteer commitment and participation.

p53/p21(WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells.

Ellagic acid is a phenolic compound present in fruits and nuts including raspberries, strawberries and walnuts. It is known to inhibit certain carcinogen-induced cancers and may have other chemopreventive properties. The effects of ellagic acid on cell cycle events and apoptosis were studied in cervical carcinoma (CaSki) cells. We found that ellagic acid at a concentration of 10(-5) M induced G arrest within 48 h, inhibited overall cell growth and induced apoptosis in CaSki cells after 72 h of treatment. Activation of the cdk inhibitory protein p21 by ellagic acid suggests a role for ellagic acid in cell cycle regulation of cancer cells.

Volunteers as adjunct researchers in a cancer prevention trial: the American Cancer Society Colon Polyp Prevention Study.

BACKGROUND: In April 1991, the Virginia Division of the American Cancer Society (ACS) initiated the feasibility phase of the Colon Polyp Prevention Study (CPPS) to determine whether a high fiber supplement would decrease new adenomatous colorectal polyp occurrence. The feasibility phase had two specific objectives: 1) to evaluate accrual and compliance to the designed protocol and 2) to evaluate and demonstrate the effectiveness of volunteers as research assistants. The CPPS is an innovative project in which trained volunteers play a significant role in the research process. METHODS: In the CPPS, volunteer adjunct researchers (VARs) were trained to perform individual dietary data collection and intervention and other general study monitoring functions. VARs were trained, certified, and monitored in the performance of their assigned tasks by ACS staff and expert consultants. RESULTS: A total of 119 volunteers were trained as VARs, 74 of whom were certified and matched to a study participant. Between 1991-1995, only six VARs left the study. After active accrual of participants to the study ceased in 1995, 38 VARs (50% of the certified VARs) continued to monitor the active study participants. All VARs were consistently able to conduct the functions for which they were trained. CONCLUSIONS: In spite of expected volunteer attrition rates, a core of 38 dedicated VARs were matched to 72 participants and demonstrated the ability to perform selected data collecting activities on a consistent and efficient basis. The use of trained volunteers has allowed the CPPS to function in its feasibility phase at personnel cost considerably less than that of other similar cancer prevention trials.

The effect of all-trans and 9-cis retinoic acid on the steady state level of HPV16 E6/E7 mRNA and cell cycle in cervical carcinoma cells.

Retinoids, including natural vitamin A and its analogs, have been closely studied as chemopreventive drugs. The mechanism of action of retinoids, however, is not completely understood. Our study evaluated the effects of all-trans (high affinity ligand for both RAR and RXR receptors) and 9-cis retinoic acid (binds only with RXR receptors) on E6-E7 transcription, cell proliferation, cell cycle distribution, and p53 expression in CaSki cells, a cell line derived from cervical carcinoma containing 600 copies of the HPV-16 genome. Using quantitative RT-PCR analysis, we found that CaSki cells treated with all trans retinoic acid (ATRA) for seven days had a remarkably low level of E6-E7 transcription at 10(-5) M to 10(-9) M concentrations. A smaller inhibitory effect was observed on the E6-E7 transcription at a concentration of 10(-5) M with only 9-cis retinoic acid. Flow cytometric analysis revealed that cells treated with both all trans and 9-cis RA showed an increase in the mean percentage (93.5% and 86.1% respectively) of cells in the G1 phase as compared to untreated CaSki cells (55%) and normal keratinocytes (58%). The percentage of cells in the S phase decreased from a mean percentage of 28 and 26.5 to 5.8 and 5, respectively, after treatment with all trans retinoic acid and 9-cis retinoic acid. An increase in the level of immunophenotypic expression of wild type p53 was also noted after treatment with all trans retinoic acid and 9-cis retinoic acid. All trans and 9-cis retinoic acid may act on highly proliferating tumor cells by initially arresting DNA synthesis and inducing G1 arrest. In addition, they may be inducing a p53 dependent cell cycle arrest and thus suggests that all-trans and 9-cis retinoic acid may have a cytostatic effect rather than a cytotoxic effect on CaSki cells. The increased expression of p53 positive cells and the inhibition of E6/E7 transcription after treatment with these retinoids may indicate the potential role of all trans and 9-cis retinoic acid as a cell cycle regulator and an antiviral chemoprevention agent.

Feasibility of using volunteer research staff to deliver and evaluate a low-fat dietary intervention: the American Cancer Society Breast Cancer Dietary Intervention Project.

This report presents the results of a study to examine the feasibility of using volunteers as research staff for a randomized trial of whether reduction in dietary fat intake could prevent or delay breast cancer recurrence. We examined whether volunteers could be trained to recruit study participants, deliver a complex and intensive dietary intervention, and monitor intervention effectiveness. Volunteers, who were mostly employed nurses and dietitians, screened 521 women, of whom 293 were eligible and 144 were randomized. Participants were postmenopausal women under age 75, who had recently been diagnosed with breast cancer and treated with either mastectomy or lumpectomy. At 1 year postrandomization, 77% of intervention and 75% of control participants remained active in the study. Intervention effects (change in intervention group minus change in control group) at 3, 6, and 12 months postrandomization were 5.9, 8.4, and 7.2% energy from fat and 1.7, 3.0, and 3.5 kg body weight (all P < 0.001). These results were similar to those from other studies that used paid, professional staff to deliver and monitor interventions. Results from this feasibility study suggest that volunteer-based health organizations can provide research opportunities for health practitioners and can conduct high-quality research at lower costs.

Cancer, cancer cachexia, and diet: lessons from clinical research.

Cachexia is a common cause of morbidity and mortality in cancer patients. Successful nutritional repletion might enhance treatment results, quality of life, and survival. In the past, attempts at nonvolitional feeding (enteral and parenteral techniques) have not been as successful as initially hoped. The cachectic cancer patient's loss of lean body mass has been very difficult to restore, although fat can be repleted. Laboratory and epidemiologic investigations have suggested that dietary calories and dietary fat may play a promotional role in cancer. Overfed animals and obese humans both have an increased tendency for development of malignancy. Breast cancer has been investigated extensively for its relationship to diet. Certain fatty acids appear to stimulate breast cancer, as do obesity-related changes in circulating hormones. Obesity in breast cancer and weight gain on adjuvant therapy may therefore be adverse prognostic signs. Clinical trials of decreasing dietary fat as an adjuvant to breast cancer therapy are in progress. The current challenge in nutritional management of the cancer patient is to incorporate laboratory, epidemiologic, and clinical data into a successful repletion strategy. It seems unlikely that traditional methods of supplying excess calories will succeed, so that other, more specific nutritional manipulations should be evaluated in clinical trials.

Diet and chemoprevention of colon polyps and colorectal cancer.

Clinical trials in colorectal cancer prevention are based on carcinogenesis research and epidemiologic observations that relate certain macronutrients, micronutrients, non-nutritive factors in foods, and synthetic chemicals to colon neoplasms. These factors appear to act at various points along the putative normal mucosa --> adenomatous polyp --> cancer sequence. This gives an opportunity to develop innovative clinical trails, both in agent selection and in the use of intermediate markers. Clinical colorectal cancer prevention trials are not in progress that employ dietary fiber, a variety of vitamins and minerals and several synthetic drugs, especially the NSAIDs. Most of these trials use the adenomatous polyp as a surrogate marker for colon cancer, thereby reducing trial duration, number of subjects required and overall expense. This paper is a brief review of the basic and epidemiologic background for colorectal cancer prevention trials and their current status.

Cancer prevention clinical trials.

Many kinds of cancer are preventable. Avoidance of tobacco would essentially eliminate lung cancer and most head and neck cancers as well. Other common cancers (breast, colon, prostate) are related to diet and therefore may also be preventable, at least in part. Abundant epidemiologic and laboratory data link specific nutrients including fat, fiber and vitamins to cancer so that appropriate manipulation of these constituents might reduce cancer risk. Determination of appropriate manipulations requires prospective clinical trials in humans. Approximately 40 such trials are in progress. Some have been completed with encouraging results. Future large scale trials will require designs that overcome the barriers of cost, large subject numbers and long study duration. The use of "intermediate markers" rather than cancer end points is a strategy that will help overcome these barriers.

Special aspects of cancer prevention trials.

The results of early cancer prevention trials now are being reported, and new trials have begun or are being designed. Initial trials used agents such as vitamins and minerals, generally regarded as safe. The trials in progress are using similar agents or macronutrient manipulation, but some have incorporated drugs with low but definite toxic potential, such as tamoxifen. Appropriate prevention trial design requires careful consideration of agent toxicity and the use of such agents in healthy individuals. Full disclosure of risks and benefits to potential subjects is necessary. Other considerations are study duration (usually very long) and subject number (usually very large), both of which increase the cost of a trial. Successful prevention trials must overcome these barriers through innovative design. Possible innovations include the use of intermediate marker end-points, the enrollment of subjects at high risk for a specific cancer, and the use of volunteers to help conduct trials.

Cancer prevention clinical trials.

If external factors other than tobacco (e.g., diet, sunlight) are responsible in a major way for some cancers, then appropriate manipulation and alteration of such factors should decrease the rate of these cancers. Clinical trials in cancer prevention are an attempt to test this approach. Prevention trials are based on knowledge gained from the laboratory and from epidemiology, and they are the only way to conclusively demonstrate the effectiveness of a given prevention intervention in humans. This article discusses the development of prevention trials and specific current and future trials.

Garlic: a review of its relationship to malignant disease.

Garlic (Allium sativum) has had an important dietary and medicinal role for centuries. It is now known that garlic contains chemical constituents with antibiotic, lipid-lowering, detoxification, and other medicinal effects in the body. This article reviews some of the physiological characteristics of garlic and examines the relationship between garlic and cancer prevention and treatment. Hypotheses regarding the possible role of garlic in modulating mechanisms that may alter the carcinogenic process are discussed.