Treatment Response to Lycopene in Recurrent Prostate Cancer Confirmed on 18 F-Fluciclovine PET/CT.

ABSTRACT: 18 F-fluciclovine (Axumin; Blue Earth Diagnostics, Ltd, Oxford, United Kingdom) PET has shown value in detecting biochemical recurrent prostatic cancer. Lycopene, a plant-based carotenoid, is reported to have potential inhibitory effect on prostate cancer, as a complementary treatment. We report a case of biochemically recurrent prostate cancer showing treatment response to lycopene as seen on an 18 F-fluciclovine PET/CT correlating with serum prostate-specific antigen response.

Modulation of inflammation by phytochemicals to enhance efficacy and reduce toxicity of cancer chemotherapy.

Treatment of cancer with chemotherapeutic drugs is associated with numerous adverse effects as well as the eventual development of resistance to chemotherapy. There is a great need for complementary therapies such as botanicals and nutritional supplements with little or no side effects that prevent resistance to chemotherapy and reduce its adverse effects. Inflammation plays a major role in the development of chemoresistance and the adverse effects of chemotherapy. Phytochemicals have well-established anti-inflammatory effects; thus, they could be used as complementary therapies along with chemotherapy to increase its efficacy and reduce its toxicity. Botanical compounds inhibit the NF-κB signaling pathway, which plays an important role in the generation of inflammation, chemotherapy resistance, and modulation of cell survival and apoptosis. Botanicals have previously been studied extensively for their cancer chemopreventive activities and are generally considered safe for human consumption. The present review focuses on the modulation of inflammation by phytochemicals and their role in increasing the efficacy and reducing the toxicity of cancer chemotherapy.

Walk More, Eat Less, Don't Stress.

Unhealthy diet, obesity, lack of physical activity, and psychologic stress are associated with increased inflammation, oxidative stress, insulin resistance, and DNA methylation, which are the main mechanisms of chronic diseases such as cancer, hypertension, diabetes, cardiovascular disease, and Alzheimer's disease. It has recently been found that healthy diet and physical activity can reduce inflammatory markers and improve insulin sensitivity resulting in better survivorship outcomes in patients with prostate cancer. An "anti-inflammatory" lifestyle, including physical activity, healthy body weight, healthy diet, and stress reduction, has been associated with decreased cancer risk and progression. Epigenetic changes due to DNA methylation and altered gene expression associated with unhealthy lifestyle can be modulated by healthy behaviors. National Center for Complementary and Integrative Health (NCCIH) focuses on healthy lifestyle, and it supports research on psychologic and physical approaches including dietary supplements and plant-based products, as well as mind and body approaches, such as yoga, massage, meditation, mindfulness-based stress reduction, and acupuncture. See related article by Langlais et al., p. 1760.

Awareness, Use and Outlook of Complementary and Alternative Medicine (CAM) Options in an Underserved, Uninsured Minority Cancer Patient Population.

Integrative oncology aims to coordinate the delivery of conventional medicine and evidence-supported complementary and alternative medicine (CAM) to patients receiving cancer care. This field developed out of an increased interest in CAM usage among cancer patients. However, CAM use among medically underserved cancer patients remains to be well characterized. We evaluated CAM awareness as well as prevalence and characteristics of CAM use in 170 consecutive, medically underserved cancer patients presenting to a large, academic, inner-city cancer clinic, using a survey tool. Fifty-three participants declined participation and 17 survey results were incomplete. Therefore, 100 survey results were included in the final analysis. There were 65 males and 35 females in the survey with a mean age of 64.2 years. About 98% of the respondents were African American while 2% identified themselves as Hispanic. About 45% of patients had metastatic cancer, 24% had early-stage disease while 31% of patients were not aware of the stage of their cancer. About 55% patients had elementary school or lower level of education while only 16% had a college degree or higher. About 92% of respondents were unemployed. Some knowledge of CAM was reported by 22% of patients, while CAM use was reported in only 16% of patients. Female sex and college degree were significantly associated with CAM use. The most commonly used CAM modality was meditation (56%), followed by herbal remedies (31%), yoga (31%), and acupuncture (12%). Among CAM users, a majority used multiple CAM therapies. All users reported benefit from CAM use. Emotional wellbeing was the most common benefit followed by improvement in treatment related adverse effects, chemotherapy related symptoms, pain, and sleep. Even though the majority of our surveyed patients never used CAM, 90% of non-users were interested in gaining more information about the various CAM options and exploring its use and potential benefits. The majority (70%) wanted their primary oncologist to provide information about CAM options and discuss its safety and potential complementary benefit in management of their cancer and associated symptoms.

Soy Isoflavones in Integrative Oncology: Increased Efficacy and Decreased Toxicity of Cancer Therapy.

Soy consumption in human diet has been linked to decreased incidence of a variety of cancers, suggesting a potential role of soy products in cancer prevention and control. Furthermore, a substantial body of evidence in the literature suggests that soy supplementation may improve the efficacy and prevent the adverse effects of cancer chemotherapy and radiation therapy. Isoflavones constitute the predominant anticancer bioactive compounds in soy. Genistein, which is the most abundant and active isoflavone in soy, has a multitude of effects on cancer cells, including inhibition of NF-κB activation and DNA methylation, enhancement of histone acetylation, inhibition of cell growth and metastasis, and antiangiogenic, anti-inflammatory, and anti-oxidant effects. Isoflavones are orally bioavailable, easily metabolized, and usually considered safe. In this article, we review in vitro and in vivo evidence as well as the results of clinical and epidemiological studies on the effects of soy isoflavones, with a focus on sensitization of cancer cells to chemotherapy and radiation while at the same time protecting normal cells from the harmful effects of these treatments.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Bladder Preservation With Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial.

PURPOSE: Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. METHODS: Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. RESULTS: From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. CONCLUSION: Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.

A Comprehensive Definition for Integrative Oncology.

Background: Integrative oncology, which is generally understood to refer to the use of a combination of complementary medicine therapies in conjunction with conventional cancer treatments, has been defined in different ways, but there is no widely accepted definition. We sought to develop and establish a consensus for a comprehensive definition of the field of integrative oncology. Methods: We used a mixed-methods approach that included a literature analysis and a consensus procedure, including an interdisciplinary expert panel and surveys, to develop a comprehensive and acceptable definition for the term "integrative oncology." Results: The themes identified in the literature and from the expert discussion were condensed into a two-sentence definition. Survey respondents had very positive views on the draft definition, and their comments helped to shape the final version. The final definition for integrative oncology is: "Integrative oncology is a patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, quality of life, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before,during, and beyond cancer treatment." Conclusions: This short and comprehensive definition for the term integrative oncology will facilitate a better understanding and communication of this emerging field. This definition will also drive focused and cohesive effort to advance the field of integrative oncology.

Effects of genistein supplementation on genome­wide DNA methylation and gene expression in patients with localized prostate cancer.

Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. We investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy using Illumina HumanMethylation450 and Illumina HumanHT-12 v4 Expression BeadChip Microarrays. The present study was a randomized, placebo-controlled, double-blind clinical trial on Norwegian patients who received 30 mg genistein or placebo capsules daily for 3-6 weeks before prostatectomy. Gene expression changes were validated by quantitative PCR (qPCR). Whole genome methylation and expression profiling identified differentially methylated sites and expressed genes between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation and transcriptional regulation. Enrichment analysis suggested overall reduction in MYC activity and increased PTEN activity in genistein-treated patients. These findings highlight the effects of genistein on global changes in gene expression in prostate cancer and its effects on molecular pathways involved in prostate tumorigenesis.

The impact of psychological distress during pregnancy on the developing fetus: biological mechanisms and the potential benefits of mindfulness interventions.

The in utero environment plays an essential role in shaping future growth and development. Psychological distress during pregnancy has been shown to perturb the delicate physiological milieu of pregnancy, and has been associated with negative repercussions in the offspring, including adverse birth outcomes, long-term defects in cognitive development, behavioral problems during childhood and high baseline levels of stress-related hormones. Fetal epigenetic programming, involving epigenetic processes, may help explain the link between maternal prenatal stress and its negative effects on the child. Given the potential long-term effects of early-life stress on a child's health, it is crucial to minimize maternal distress during pregnancy. A number of recent studies have examined the usefulness of mindfulness-based programs to reduce prenatal psychological stress and improve maternal psychological health, and these are reviewed here. Overall, the findings are promising, but more research is needed with large studies using randomized controlled study designs. It remains unclear whether or not such interventions could also improve child health outcomes, and whether these changes are modulated at the epigenetic level during fetal development. Further studies in this area are needed.

Ginger augmented chemotherapy: A novel multitarget nontoxic approach for cancer management.

Cancer, referred to as the 'disease of civilization', continues to haunt humanity due to its dreadful manifestations and limited success of therapeutic interventions such as chemotherapy in curing the disease. Although effective, chemotherapy has repeatedly demonstrated inadequacy in disease management due to its debilitating side effects arising from its deleterious nonspecific effects on normal healthy cells. In addition, development of chemoresistance due to mono-targeting often results in cessation of chemotherapy. This urgently demands development and implementation of multitargeted alternative therapies with mild or no side effects. One extremely promising strategy that yet remains untapped in the clinic is augmenting chemotherapy with dietary phytochemicals or extracts. Ginger, depository of numerous bioactive molecules, not only targets cancer cells but can also mitigate chemotherapy-associated side effects. Consequently, combination therapy involving ginger extract and chemotherapeutic agents may offer the advantage of being efficacious with reduced toxicity. Here we discuss the remarkable and often overlooked potential of ginger extract to manage cancer, the possibility of developing ginger-based combinational therapies, and the major roadblocks along with strategies to overcome them in clinical translation of such inventions. We are optimistic that clinical implementation of such combination regimens would be a much sought after modality in cancer management.

Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds.

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.

Lycopene in the prevention of renal cell cancer in the TSC2 mutant Eker rat model.

Renal cell carcinoma (RCC) is the most frequent upper urinary tract cancer in humans and accounts for 80-85% of malignant renal tumors. Eker rat represents a unique animal model to study RCC since these rats develop spontaneous renal tumors and leiomyoma, which may be due to tuberous sclerosis 2 (TSC2) mutation resulting in the activation of the mammalian target of rapamycin (mTOR) pathway. This study examines the role of a lycopene-rich diet in the development of RCC in the TSC2 mutant Eker rat model. Ten-week old female Eker rats (n=90) were assigned in equal numbers to receive 0, 100 or 200mg/kg of lycopene as part of their daily diet. After 18 months the rats were sacrificed and the kidneys were removed. Immunohistochemical staining with antibodies against mTOR, phospho-S6 and EGFR were performed, as well as hematoxylin-eosin staining for histologic examination of the tumors. Tumors were counted and measured in individual kidneys. Presence of tumor decreased from 94% in control animals to 65% in the experimental group, but the difference was not statistically significant (P<0.12). However, mean numbers of renal carcinomas were statistically significantly decreased in the lycopene-treated rats (P<0.008) when compared to untreated controls. In the lycopene group, tumor numbers decreased (P<0.002) and the numbers tended to decrease linearly (P<0.003) as supplemental lycopene increased from 0 to 200. Control rats fed only basal diet had a greater length of tumors (23.98 mm) than rats fed lycopene supplement groups (12.90 mm and 11.07 mm) (P<0.05). Moreover tumor length decreased (P<0.02) and tumor length tended to decrease linearly (P<0.03) as supplemental lycopene increased from 0 to 200mg/kg. All tumors showed strong staining with antibodies against mTOR, phospho-S6 and EGFR. In conclusion, dietary supplementation with lycopene attenuates the development of renal cell cancers in the predisposed TSC2 mutant Eker rat model. These results suggest that lycopene may play a role in the prevention of RCC.

Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival.

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on "Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment" was conducted at the Moffitt Cancer Center, 29­31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop.

Selenium in the prevention of anthracycline-induced cardiac toxicity in children with cancer.

High cumulative doses of anthracyclines (300-500 mg/m(2)) used in the treatment of children with cancer may result in cardiotoxicity, a major long-term adverse effect that limits clinical usefulness of this class of chemotherapeutic agents. We assessed anthracycline-induced cardiotoxicity by measuring Pro-BNP levels and echocardiographic (ECHO) findings and investigated potential protective effect of selenium (Se) supplementation in a group of pediatric cancer patients. Plasma level of Pro-BNP was measured, and ECHO was performed in 67 patients (45 boys, 22 girls; ages 2-18 years; median age 12 years) after they completed anthracycline-containing chemotherapy. Serum Se level was measured in 37 patients. Eleven patients had high Pro-BNP levels and/or cardiac failure with Pro-BNP levels of 10-8,022 pg/mL (median 226.3 pg/mL; laboratory normal level is less than 120 pg/mL). Serum Se levels were low (20-129 mcg/L, median 62 mcg/L) in ten of these eleven patients. Eight of 10 patients with low Se and high Pro-BNP levels were supplemented with Se 100 mcg/day for a period of 4-33 months (median 6 months) which resulted in improvement in Pro-BNP and/or ECHO findings. These results suggest that Se supplementation may have a role in protection against anthracycline-induced cardiac toxicity.

Tomato powder impedes the development of azoxymethane-induced colorectal cancer in rats through suppression of COX-2 expression via NF-κB and regulating Nrf2/HO-1 pathway.

Cancer is one of the leading causes of death worldwide. Since dietary factors have been connected to a reduced risk of a diversity of human cancers, in this study we investigated the effects of tomato powder (TP) on the development of azoxymethane (AOM)-induced colorectal cancer in Wistar rats, and possible mechanism(s) by which TP shows its chemopreventive activity. Here we show that TP added to feed at 5% rate decreases the rate of aberrant crypt foci (ACF) and reduces the development of adenocarcinoma and growth of AOM-induced colorectal cancer in rats. In addition, we demonstrate that TP supplementation shows its chemopreventive activities through inhibition of cyclooxygenase-2 (COX-2) expression via NF-κB pathway and promotion of apoptosis, as well as regulating Nrf2/HO-1 signaling pathway in colorectal tissue of AOM-treated rats. Our findings identify an intimate connection between dietary supplementation of TP and the decreased risk of colorectal cancer in rats, and suggest that consumption of TP would be a natural candidate for the prevention of colorectal cancer in men.

Inhibitory effects of combination of lycopene and genistein on 7,12- dimethyl benz(a)anthracene-induced breast cancer in rats.

Breast cancer is one of the most common cancers in women. Carotenoids and soy isoflavones have been postulated to have breast cancer preventive effects. We investigated the potential preventive effects of lycopene and genistein, alone and in combination, on breast cancer development in female Wistar rats treated with 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogen known to induce breast tumors. Mammary carcinogenesis was initiated by a single, oral gavage of DMBA (80 mg/kg body weight) at 55 days of animal age. Fifty female Wistar rats were divided into 5 experimental groups having 10 animals per group: Group 1 (normal control), Group 2 (DMBA control), Group 3 (DMBA + lycopene), Group 4 (DMBA + genistein), and Group 5 (DMBA + lycopene and genistein). Rats were fed either lycopene (20 mg /kg bw) or genistein (2 mg /kg bw) by oral gavage (3 times per week) starting 2 wk prior to DMBA injection. Treatment was continued for 20 wk. Rats treated with DMBA developed mammary tumors with 100% tumor incidence during the 20-wk study. Inhibition of mammary cancer incidence by lycopene (70%), genistein (60%) and their combination (40%) was observed. Tumor weight decreased by 48%, 61%, and 67%, and mean tumor volume decreased by 18%, 35%, and 65% with lycopene, genistein, and lycopene + genistein, respectively (P < 0.01 for the combination). The proportions of adenocarcinoma masses decreased with lycopene and genistein combination (P < 0.05). Administration of lycopene and genistein combination suppressed breast cancer development and was associated with a decrease in MDA, 8-isoprostane, and 8-OhdG levels and with an increase in serum lycopene and genistein levels. Animals administered DMBA developed breast cancer, which was associated with increased expression of Bcl-2 and decreased expression of Bax, caspase 3, and caspase 9 in mammary tissues. Administration of genistein and lycopene in combination was more effective in inhibiting DMBA-induced breast tumors and modulating the expression of apoptosis associated proteins than the administration of each agent alone. Our results suggest that lycopene and genistein are potent antioxidants and, when given in combination, offer maximum protection against DMBA-induced mammary carcinogenesis.

Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial.

We conducted a placebo-controlled, block-randomized double-blind Phase 2 study to examine the effect of 30 mg synthetic genistein daily on serum and tissue biomarkers in patients with localized prostate cancer (CaP). Fifty-four study subjects were recruited and randomized to treatment with genistein (n = 23) or placebo (n = 24) for 3 to 6 wk prior to prostatectomy. Seven study subjects were noncompliant to the study protocol. Adverse events were few and mild. Serum prostate specific antigen (PSA) decreased by 7.8% in the genistein arm and increased by 4.4% in the placebo arm (P = 0.051). The PSA level was reduced in tumor tissue compared to normal tissue in the placebo arm. In the genistein arm, the PSA level in tumor and normal tissue was comparable. Total cholesterol was significantly lower in the genistein arm (P = 0.013). There were no significant effects on thyroid or sex hormones. Plasma concentrations of total genistein were on average 100-fold higher in the genistein arm after treatment (P < 0.001). Genistein at a dose that can be easily obtained from a diet rich in soy reduced the level of serum PSA in patients with localized CaP, without any effects on hormones. It was well tolerated and had a beneficial effect on blood cholesterol.

Clinical trials of antioxidants as cancer prevention agents: past, present, and future.

The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included ß-carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials.