The circadian timing system (CTS) coordinated by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of behavior, physiology, as well as cellular metabolism and proliferation. Altered circadian rhythms predict for poor survival in cancer patients. An increased incidence of several cancers has been reported in flight attendants and in shift workers. To explore the contribution of the CTS to tumor growth, we developed experimental models of disrupted or enhanced circadian coordination through stereotaxic destruction of the SCN, modifications of photoperiodic or feeding synchronizers and/or the administration of pharmacologic agents. SCN ablation or exposure to experimental chronic jetlag (CJL, consisting of an 8-hour advance of the light-dark cycle every 2 days) caused alterations in circadian physiology and significantly accelerated tumor growth. CJL suppressed or altered the rhythms of clock gene and cell cycle gene expression in mouse liver. It increased p53 and decreased c-Myc expression, a result in line with the promotion of diethylnitrosamine -initiated hepatocarcinogenesis in jet-lagged mice. The accelerating effect of CJL on tumor growth was counterbalanced by the regular timing of food access over the 24-h. Meal timing prevented the circadian disruption produced by CJL and slowed down tumor growth. In synchronized mice, meal timing reinforced host circadian coordination, phase-shifted the transcriptional rhythms of clock genes in the liver of tumor-bearing mice and slowed down cancer progression. These results support the role of the CTS in cancer progression and call for the development of therapeutic strategies aimed at preventing or treating circadian clock dysfunctions.

In the article "Inhibitive Effect of Artemether on Tumor Growth and Angiogenesis in the Rat C6 Orthotopic Brain Gliomas Model", Zhi-ping Wu et al., published in the March 2009 issue (Integrative Cancer Therapies, 8(1):88-92; first published on January 27, 2009, doi: 10.1177/1534735408330714), the name of the corresponding author was incorrectly published as Zhi-ping Wu. The corresponding author for the article is Qi-shun Zhu, 2#Cuifu Northern Road, Kunming 650091, China; e-mail: qshzhu@ynu.edu.cn. This has been published for the convenience of the reader and the authors.

In the article "Effects of a Yoga Program on Cortisol Rhythm and Mood States in Early Breast Cancer Patients Undergoing Adjuvant Radiotherapy: A Randomized Controlled Trial", published in the March 2009 issue (Integrative Cancer Therapies,8(1):37-46; first published on February 3, 2009, doi: 10.1177/1534735409331456), the name of the first author was incorrectly published as Rao M. Raghavendra. The first author of the article is H.S. Vadiraja and Rao M. Raghavendra is the corresponding author for the article.

In the article "Effect of Withaferin A on the Development and Decay of Thermotolerance in B16F1 Melanoma: A Preliminary Study" by Kalthur et al, published in the March 2009 issue (Integrative Cancer Therapies, 8(1):93-97; first published on February 3, 2009, doi: 10.1177/1534735408330715), data in the abstract appeared incorrectly. The abstract below has been reprinted with the correct data.

This article provides a bibliography of the scientific publications of John Beard, DSc (1858-1924). Beard was an English embryologist and cancer researcher of the late 19th and early 20th century, who devised the trophoblastic theory of cancer, a forerunner of today's theory of cancer stem cells. Beard was the author of more than 100 scientific articles and monographs, as well as the book The Enzyme Treatment of Cancer (1911). This is the first bibliography ever compiled of his scientific publications.

Systemic enzyme therapy was recently subjected to experimental investigations and to rigorous clinical studies in cancer patients. The designs of the relevant clinical cohort studies followed the guidelines of Good Epidemiological Practice and represent level IIB in evidence-based medicine (EBM). Scientifically sound experimental in vitro and in vivo investigations are far advanced and document promising immunological, anti-inflammatory, anti-infectious, and antitumor/antimetastatic activities of proteolytic enzyme mixtures (containing trypsin, chymotrypsin, and papain) or bromelain. EBM level II clinical studies, which are accepted by the European Union to show safety and efficacy of medical treatments, were performed to evaluate the benefit of complementary systemic enzyme therapy in cancer patients suffering from breast and colorectal cancers and plasmacytoma. These studies demonstrated that systemic enzyme therapy significantly decreased tumor-induced and therapy-induced side effects and complaints such as nausea, gastrointestinal complaints, fatigue, weight loss, and restlessness and obviously stabilized the quality of life. For plasmacytoma patients, complementary systemic enzyme therapy was shown to increase the response rates, the duration of remissions, and the overall survival times. These promising data resulted in an "orphan drug status" designation for a systemic enzyme product, which should motivate further studies on this complementary treatment.

In this monograph, the chemopreventive effects of enterally administered proteases (trypsin, chymotrypsin, and papain) have been documented in a series of animal experimental tumor models. The experimental evidence demonstrates a significant inhibition of growth of both the primary tumor and the metastatic disseminations. Survival in animals treated with proteases is significantly longer than in untreated animals. The results confirm the fundamental correlation between early initiation of therapy and consequent growth of the tumorous disease. Comparable results have been shown in solid tumors in animal models (melanoma and Lewis lung carcinoma) and in human tumors (pancreatic and breast cancers). In this article, details of the known mechanisms of systemic actions of enterally administered proteases are documented and their relationship with cancerogenesis is discussed.

The supporting role of proteases in tumor progression and invasion is well known; however, the use of proteases as therapeutic agents has also been demonstrated. In this article, the authors report on the differential effects of exogenous serine proteases on the motility of tumor and normal cells. The treatment of normal and tumor cells with a single dose of pancreatic serine proteases, trypsin (TR) and chymotrypsin (CH), leads to a concentration-dependent response by cells, first accelerating and then slowing mobility. Tumor cells are 10 to 20 times more sensitive to exogenous TR/CH, suggesting that a single dose of proteases may cause discordant movements of normal and tumor cells within the tumor environment. The inhibitory effects of TR on cell motility are contradicted by thrombin (TH), particularly in the regulation of normal cells' migration. The purpose of this investigation was to ascertain the role of protease-activated receptors (PARs) in terms of normal and tumor cell motility. Duplicate treatments with proteases resulted in diminished mobility of both normal and tumor cells. Repeated application of TR and TH in 1-hour treatment intervals initially desensitizes cell surface PARs. However, cell surface PARs reappear regardless of subsequent protease treatments in both normal and tumor cells. The resensitization process is retarded in tumor cells when compared with normal cells. This is evidenced by lower expression of PARs as well as by their relocalization at the tumor cell surfaces. Under these conditions, normal cells remain responsive to exogenous proteases in terms of cell motility. Exogenous proteases do not modulate motility of repeatedly stimulated tumor cells, and consequently, the migration of tumor cells appears disconnected from the PAR signaling pathways. The use of activating peptides in lieu of the cognate proteases for a given PAR system indicated that proteases may act through additional targets not regulated by PAR signaling. We hypothesize that the divergent migration patterns of normal and tumor cells due to exposure to proteases is in part mediated by PARs. Thus, treatment with exogenous proteases may cause rearrangement of the tumor and stromal cells within the tumor microenvironment. Such topographical effects may lead to the inhibition of tumor progression and metastasis development.

The trophoblastic theory of cancer, proposed in the early 1900s by Dr John Beard, may not initially seem relevant to current cancer models and treatments. However, the underpinnings of this theory are remarkably similar to those of the cancer stem cell (CSC) theory. Beard noticed that a significant fraction of germ cells never reach their final destination as they migrate during embryonic development from the hindgut to the germinal ridge. In certain situations, upon aberrant stimulation, these vagrant germ cells are able to generate tumors. Simplistically, the CSC theory surmises that a small population of tumorigenic cells exists, which initiate and maintain tumors, and these cells have a likely origin in normal stem cells. Both these theories are based on the potential of a single primitive cell to form a tumor. This has a major implication for cancer therapy, in that only a small percentage of cells need to be targeted to ablate a tumor.

In the early 20th century, advocacy of the enzyme therapy of cancer was primarily the work of one man, John Beard, DSc (1858-1924). He and his collaborators made a determined effort to establish this mode of therapy, especially in the years 1905 to 1911. Despite a brief flowering of international interest, Beard's efforts came to naught. During the 20th century, there was a succession of American researchers who continued to investigate this topic. This included Marshall William McDuffie, MD (1882-1945), Frank LeForest Morse, MD (1876-1953), Franklin Lloyd Shively, MD (1887-1971), and William Donald Kelley (1926-2005). In central Europe, India, and other parts of the globe, the use of pancreatic enzymes as an adjuvant treatment for cancer has become a fairly routine practice, at least among those doctors who utilize complementary and alternative medicine (CAM). It is also a well-established method for reducing inflammation and mitigating the adverse effects of cytotoxic treatment.

The British developmental biologist John Beard, DSc (1858-1924) is little remembered today. Yet, he made outstanding contributions to the life sciences. Beard deserves to be included among the leading biologists of the late 19th and early 20th century. He has been hailed as a forerunner of the present-day theory of the cancer stem cell (CSC). He was the first to point to the parallels between cancer and the trophoblastic cells that envelop and nourish the embryo, characterizing cancer as "irresponsible trophoblast." He pointed out that the initiation of fetal pancreatic function coincided with a reduction in the invasiveness of trophoblast, which otherwise might progress to clinical cancer (ie, choriocarcinoma). Based on the above propositions, he recommended the therapeutic use of pancreatic enzymes in treating cancer and other diseases. This therapy created a worldwide controversy, and although rejected in his day, persists in the world of complementary and alternative medicine (CAM) today.

The radioprotective effect of Emblica officinalis extract (EOE) was studied in mice. Swiss albino mice were exposed to rays (5 Gy) in the absence (control) or presence (experimental) of EOE, orally 100 mg/kg body weight, once daily for 7 consecutive days. A specimen of small intestine (jejunum) was removed from the mice and studied at different autopsy intervals from 12 hours to 30 days. In control animals, crypt cell population, mitotic figures, and villus length were markedly reduced on day 1; these later started to increase progressively but did not attain the normal level even at the last autopsy interval. The animals receiving EOE prior to irradiation had a higher number of crypt cells and mitotic figures when compared with non-drug-treated control at all the autopsy intervals. Irradiation of animals resulted in a dose-dependent elevation in lipid peroxidation and a reduction in glutathione as well as catalase concentration in the intestine at 1 hour post-irradiation. In contrast, EOE treatment before irradiation caused a significant depletion in lipid peroxidation and elevation in glutathione and catalase levels.

Protein synthesis inhibitors can suppress the development of thermotolerance in tumor tissues on repeated heating. Withaferin A (WA), isolated from Withania somnifera has cytotoxic and inhibitory action on protein synthesis. In the present investigation, effect of WA on development and decay of thermotolerance in B16F1 melanoma was studied in C57BL mice. Tumors of 10010 mm3 size were subjected to repeated hyperthermia (HT) at 43°C for 30 minutes. WA was injected after first hyperthermia treatment. The tumor response was assessed by calculating the tumor growth delay (GD). The GD increased with increase in time gap between two hyperthermia treatments and was significantly higher (p < 0.05 to p < 0.001) in WA treated groups at all the respective time gaps (except at 0h and 120h) compared to hyperthermia alone group. WA increases the tumor response during repeated hyperthermia by reducing the magnitude of thermotolerance developed and by decreasing the recovery time from thermotolerance.

To explore the inhibitive effect of artemether on glioma growth and angiogenesis in brain tumor bearing SD rat. MTT assay was used to evaluate the inhibitory effect of artemether treatment on C6 glioma cells. Forty SD rats which were subcutaneous planted with SD rat C6 glioma cell to establish SD rat orthotopic glioma model were divided resourcefully into 5 groups. each group was 8 rats. Length-path (a mm) and short-path (b mm) of tumor each rat was measured. Tumor volume was calculated using the following formula: V (mm³) = a²b_/6. Microvessel density (MVD) in different therapy groups was significantly lower than that in normal saline control group and brain glioma volume in different therapy groups was significantly smaller than that in normal saline control group. There were remarkably inhibitory effects of artmeter on brain glioma growth and angiogenesis in SD rats and the mechanism that artemether inhibited brain glioma growth might be penetrating the blood-brain barrier and inhibiting angiogenesis.

The authors investigate the antiangiogenic and proapoptotic effects of mustard essential oil containing allyl isothiocyanate (AITC) and explore its mechanism of action on Ehrlich ascites tumor (EAT) cells. Swiss albino mice transplanted with EAT cells were used to study the effect of AITC. AITC was effective at a concentration of 10 µm as demonstrated by the inhibition of proliferation of EAT cells when compared with the normal HEK293 cells. It significantly reduced ascites secretion and tumor cell proliferation by about 80% and inhibited vascular endothelial growth factor expression in tumor-bearing mice in vivo. It also reduced vessel sprouting and exhibited potent antiangiogenic activity in the chorioallantoic membrane and cornea of the rat. AITC arrested the growth of EAT cells by inducing apoptosis and effectively arrested cell cycle progression at the G1 phase. The results clearly suggest that AITC inhibits tumor growth by both antiangiogenic and proapoptotic mechanisms.

Background: HESA-A is a natural biological compound of herbal—marine origin. The aim of this study was to investigate the therapeutic effects of HESA-A in patients with metastatic colon cancer. Methods: Fifty consecutive patients with end-stage colon cancer and liver metastasis at the Cancer Research Center of Tehran University of Medical Sciences were studied. Patients received HESA-A 50 mg/kg/d orally in 2 to 3 divided doses for 6 months. The patients were assessed at the start and end of the 1st, 2nd, 4th, 8th, 12th, 16th, 20th, and 26th weeks of the study. The Karnofsky Performance Scale questionnaire was completed for each patient. Results: The mean Karnofsky performance score increased from 33.6 ± 9.8 to 63.3 ± 11 after 10 weeks of study. No significant hepatic or hematological adverse effects were seen during the study. Conclusion: It seems that HESA-A is an effective and safe anticancer drug, which can be used in selected patients.

Older patients are more likely than ever to be under the care of both physicians and complementary and alternative medicine (CAM) practitioners, yet there is little research on older patients' experience of these different relationships. This article addresses older breast cancer patients' seeking of concurrent care and examines patients' understandings of interactions with physicians and CAM practitioners. This is a qualitative study of a random, population-based sample of 44 older women with breast cancer who are simultaneously under the care of at least 1 physician and 1 CAM practitioner.

Objective: to assess the use of, knowledge about, and the demand for information concerning complementary and alternative medicine (CAM) in cancer patients. Methods: A cross-sectional survey was performed on consecutive patients visiting the outpatient tumor treatment center of a university hospital at Munich, Germany. The authors used a questionnaire with questions on sociodemographics, tumor diagnosis and treatment, current symptoms, previous use of CAM, and expectations and attitudes with respect to CAM. Results: 52% used at least 1 CAM method, 24% did not use CAM but asked for consultation, and 24% neither used CAM nor were interested; 59% rated CAM treatment as personally important; 76% and 34% described themselves as well informed about conventional treatment and CAM, respectively. Current CAM use was associated with higher degrees of information and subjective importance, and not suffering from lymphatic cancer and metastases. Conclusions: CAM is a relevant topic for the care of cancer patients.

It was hypothesized that participation in a psychosocial intervention incorporating meditation, social support, positive thinking, and a low-fat, vegetarian diet would have beneficial effects on mood, coping, and quality of life (QOL) in cancer patients. This article describes the sociodemographic, medical, and psychological characteristics of participants in a psychosocial intervention designed for cancer patients. It also describes program impact in terms of Profile of Mood States, Mini-Mental Adjustment to Cancer, and Functional Assessment of Chronic Illness Therapy. Compliance with program recommendations for 3 months and effects on adjustment were also explored. Improvements in all measures were found at program completion, with spiritual well-being particularly linked to improvement in QOL. The results suggest that the program has significant beneficial effects on adjustment but that these may not be fully maintained at follow-up, possibly because of difficulty in incorporating program recommendations into everyday life, increasing disease severity, and lack of accountability.

Objectives. This study compares the effects of an integrated yoga program with brief supportive therapy in breast cancer outpatients undergoing adjuvant radiotherapy at a cancer center. Methods. Eighty-eight stage II and III breast cancer outpatients are randomly assigned to receive yoga (n = 44) or brief supportive therapy (n = 44) prior to radiotherapy treatment. Assessments include diurnal salivary cortisol levels 3 days before and after radiotherapy and self-ratings of anxiety, depression, and stress collected before and after 6 weeks of radiotherapy. Results. Analysis of covariance reveals significant decreases in anxiety (P < .001), depression (P = .002), perceived stress (P < .001), 6 a.m. salivary cortisol (P = .009), and pooled mean cortisol (P = .03) in the yoga group compared with controls. There is a significant positive correlation between morning salivary cortisol level and anxiety and depression. Conclusion. Yoga might have a role in managing self-reported psychological distress and modulating circadian patterns of stress hormones in early breast cancer patients undergoing adjuvant radiotherapy.

Introduction: This survey aims to identify herb-chemotherapeutic drug combinations in a defined group of cancer patients and to explore possible clinical consequences of these combinations. Methods: Herb-chemotherapeutic drug combinations were identified among adult cancer patients, and clinical consequences of the combinations were explored by literature searches in medical databases on possible mutual effects on similar cytochrome P-450 metabolising enzymes (CYPs) and/or the P-glycoprotein (P-gp) transporter. Results: Among 42 cancer patients using herbal remedies concurrently with chemotherapy, 136 two-agent herb-drug combinations were registered and 47 different potential herb-drug interactions were identified on the level of CYP metabolism and P-gp transport in vitro. Garlic, ginger, green tea and noni juice were the herbal remedies most frequently used in such combinations. For 48 % of the herbal remedies identified no literature data exist on their interaction potentials. Clinical studies were available for four herbal remedies only. Minor clinical potential for CYP interactions in humans was indicated for green tea and Echinacea. P-gp interactions were only investigated for garlic, which showed a significant interaction potential both in vivo and in vitro. Conclusion: The large number of in vitro potential herb-drug interactions identified urge for more clinical pharmacokinetic interaction studies in humans.

Recommendations for a healthy or prudent diet include a large number of daily servings of fruits and vegetables, and these 2 classes of food are widely believed to assist in cancer prevention. One potential mechanism that is rarely mentioned in nutritional studies involves the cytochrome P450 enzyme CYP1B1, which appears to have the unique properties of being a universal cancer marker overexpressed in cancer cells and having the capability of converting various phytochemicals and synthetic chemicals into substances cytotoxic to these cells. Although these particular features of CYP1B1 have not gone unnoticed, there has been relatively little research aimed at exploiting them. Furthermore, therapeutic and preventive strategies currently being considered based on vaccines against the enzyme or inhibition without the generation of cytotoxins can be questioned because they do not take advantage of the unique properties of this enzyme. In addition, a few relevant case histories have been published that use specially designed fruit extracts containing substrates with demonstrated cytotoxic metabolic products, and these reports provide an initial confirmation of the potential of exploiting the unusual properties of this enzyme for cancer therapy.