Integrative Cancer Therapies

Therapeutic gain by radiotherapy can be achieved through improved targeting, selectively sensitizing malignant cells, or protecting normal tissue. The majority of synthetic chemical radiation sensitizers and normal tissue protectors have proved to be too toxic at effective clinical doses. However, Asian botanicals (from both Chinese and Ayurvedic medicine) are being evaluated for their ability to improve therapeutic gain through the modulation of reactive oxygen species. An increase in the efficacy of radiotherapy on tumor tissue allows a reduction in the dose applied to normal tissues. In addition, some botanicals may selectively protect normal tissue or increase its repair following radiation therapy. The results are promising enough to consider clinical trials.

Numerous botanical agents, many of which are used in whole medical system practices (i.e. traditional Chinese medicine, Ayurvedic medicine, etc.), have been shown to exhibit radiomodifying effects on tumors and normal tissues in-vitro and invivo studies. Some of these agents can enhance the therapeutic gain of radiation therapy by either acting as a radiosensitizer to tumor cells and/or as a radioprotector to normal cells. Botanical agents are comprised of multiple phytochemical compounds that may work individually or synergistically to not only improve radiation therapy outcomes, but may also exhibit a variety of anti-cancer effects as well. It will be important to evaluate these botanicals for efficacy, tumor specificity, and safety profiles before they can be recommended during radiation therapy.

Background. Taiwan’s National Health Insurance (NHI) is a comprehensive and universal program, providing Western medicine (WM) and Chinese medicine (CM). This study aims to explore CM use among prostate cancer patients in NHI. Methods. A cross-section retrospective analysis was conducted using registration and claim data sets from the NHI Research Database. In 2007, 22 352 prostate cancer patients with 265 497 visits of CM and WM ambulatory services were identified. Patient demographics, patterns of therapies, and costs were analyzed. Results. In 2007, 592 prostate cancer patients (2.6%) had 4141 CM outpatient visits (7.0 on average). The median age was 73.9. The majority (90.5%) of CM users also used WM ambulatory services. About one third of CM outpatient services were provided by private clinics. The most frequently used CM therapies were Chinese herbal medication (93.6%), followed by acupuncture/traumatology manipulative therapies (7.0%). CM accounted for 0.2% expenditure ($87 500) and 1.6% visits of ambulatory services. The average cost per visit for WM was 6.3 times higher than that for CM ($133.6 vs $21). Conclusions. The prevalence and costs of insurance-covered CM among prostate cancer patients were low. Most prostate cancer patients did not use insurance-covered CM. The majority of CM users also used WM. CM appeared to play a complementary rather than an alternative role.

Hypothesis: Anorexia and cancer cachexia produce significant loss of adipose tissue and muscle mass and eventually reduce survival in cancer patients. Study design: This phase II study was conducted to assess the efficacy and the safety of an herbal decoction with Astragali Radix in patients with anorexia in advanced cancer. Methods: All patients with histologic evidence of an incurable malignancy had a weight loss of at least 5% during the preceding 6 months and a patient-estimated severe anorexia.The herbal decoction was administered 30 minutes after meals, three times a day for 3 weeks.The score of appetite, body weight, the cytokines, IL-1β, IL-6, TNF-α, and anthropometric measurements were assessed. For the assessment of anorexia, a visual analog scale (VAS: 0 mm = no anorexia, 100 mm = maximal anorexia) was used. Results: Eleven patients were recruited from January, 2007 to January, 2009. The mean age was 59.8 years old. The change in anorexia from baseline with the herbal decoction was significantly different and anorexia was improved (anorexia VAS score, 60mm vs. 40mm, p = 0.008). The mean value of the maximal body weight was 55.6 kg and differed significantly from the 54.6 kg at baseline (p = 0.009). Changes in cytokine levels and anthropometric measurements from baseline to the 3rd week were not significant. All toxicities were manageable. Conclusion: Appetite and body weight were improved with the herbal decoction. This herbal decoction shows some potential for management of cancer-related anorexia.

Background: After cardiovascular disease, cancer is the most common cause of death. HESA-A is a natural product of herbal and marine origin. The aim of this study was to investigate the beneficial effects of HESA-A in patients with end-stage metastatic cancers. Methods: In this clinical trial, 30 consecutive patients (18 men, 12 women) with end-stage cancers 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 3 months. At the start and end of the 1st, 4th, 8th, and 12th weeks of the study, the patients were assessed and hematological and hepatic biochemical indices were measured. Also, the Karnofsky Performance Scale questionnaire was completed for each patient. Results: The mean age of patients was 56.23 ± 12.10 years. Mean Karnofsky Performance Scale scores of the patients increased from 48 ± 14.36 to 78.42 ± 15.37 after 12 weeks of treatment. A total of 90.4% of the patients who remained in the study were alive for 12 weeks. No significant hepatic or hematologic adverse effect was seen during the study. Conclusion: HESA-A appears to be an effective and safe anticancer compound that may increase survival of end-stage patients and can be used in selected cases. Further prospective controlled clinical trials with large sample size and longer follow-up period are warranted to understand the mechanisms of action of HESA-A and evaluate its long-term effects on the survival and quality of life of patients with cancer and as well as its unfavorable side effects.

An essential oil extract, derived from the rhizome of Curcuma wenyujin (CWE), possesses antioxidative, antimicrobial, and anti-inflammatory properties. However, it remains unknown how exactly CWE inhibits tumor growth. In this study, using human cervical cancer HeLa cells, the authors postulated that CWE has the ability to inhibit tumor growth. The study shows that CWE dose-dependently suppressed colony formation and inhibited the proliferation of HeLa cells through blockade of cell cycle progression at G1 phase and apoptosis. CWE-induced G1 arrest was associated with retinoblastoma protein dephosphorylation and reduced amounts of cyclins D1 and D3, and cyclin-dependent kinase 4 and 6 proteins. CWE treatment resulted in apoptosis in HeLa cells as evidenced by morphological changes, caspase activation and PARP cleavage, which can be reversed by a pan-caspase inhibitor. It was observed that CWE treatment activated the mitochondrial apoptotic pathway indicated by a decrease in Mcl-1 and Bcl-xL levels, resulting in mitochondrial membrane potential loss and caspases 9 activation. CWE-treated cells displayed reduced PTEN, AKT, and STAT3 phosphorylation and downregulation of NFκB signaling, providing a mechanism for the G1 arrest and apoptosis observed. Furthermore, CWE inhibited tumor growth of HeLa in a xenograft mouse tumor model, suggesting that CWE inhibited tumorigenesis by inhibiting cell proliferation and inducing apoptosis. These findings are the first to reveal the molecular basis for the anticervical cancer action of CWE. The results suggest that CWE could be developed as a drug for the management of cervical cancer.

Background. Qingyihuaji formula (QYHJ) is a widely used herbal formula that has shown promising antitumor effect in the treatment of pancreatic cancer in the Cancer Hospital, Fudan University, Shanghai, China. Objective. This research was conducted to study whether Ski acts as a therapeutic target of QYHJ formula in the treatment of SW1990 pancreatic cancer. Methods. The expression changes of Ski mRNA and protein in SW1990 pancreatic cancer subcutaneously transplanted tumor treated with QYHJ were detected by real-time polymerase chain reaction and Western blot. Then, we established a stable transfection SW1990 cell with low expression of Ski through lentivirus-mediated RNA interference (RNAi) technique. The responses to QYHJ treatment on a subcutaneously transplanted tumor with different Ski expression statuses were evaluated. Finally, the effect of Ski downregulation on SW1990 cell biological behavior was also evaluated. Results. Expression of Ski mRNA and protein in SW1990 subcutaneously transplanted tumor decreased dramatically after the treatment with QYHJ. Stable transfection cells with low expression of Ski (SW1990/Ski RNAi) were created, and negative vector-transfected cells (SW1990/con RNAi) were used as controls. The tumor weight inhibitory rates of QYHJ on subcutaneously transplanted tumors formed by SW1990 or SW1990/con RNAi were 29.6% and 32.2%, respectively, whereas they were 16.0% to 17.8% when the tumors were formed by SW1990/Ski RNAi. Ski downregulation sensitized the response of SW1990 cells to TGF-β1-induced growth inhibition in vitro. Flow cytometric analyses revealed that the percentage of cells in the G1 phase increased from 40.4% to 62.9% when Ski was downregulated. The subcutaneously transplanted tumors formed by SW1990/Ski RNAi grew much more slowly than those formed by parental and control vector—transfected cells. Conclusion. Ski acts as therapeutic target of QYHJ in the treatment of SW1990 pancreatic cancer cells, and its expression status mediates different responses to QYHJ treatment.

The aim of this study was to determine the effects of ¹²⁵I seeds on prostate carcinoma (PC3) cells. The relative biological effectiveness of ¹²⁵I seeds on PC3 cells with respect to ⁶⁰Co γ rays was 1.4. Both 4 Gy of ⁶⁰Co γ ray and ¹²⁵I seed irradiation increased the percentage of cells in G₂ phase, but there was no significant difference between these 2 types of radiation. Significantly, ¹²⁵I seeds induced higher apoptotic rates of PC3 cells compared with ⁶⁰Co γ ray irradiation. Furthermore, Bcl-2 expression, but not caspase-3 activity, in PC3 cells was downregulated after irradiation with ¹²⁵I seed or ⁶⁰Co γ rays.

Tocotrienols of palm oil have been shown to possess potent neuroprotective, antioxidative, anticancer, and cholesterol-lowering activities. In this study, the authors examined the antiproliferative effects of α-, γ- and δ-tocotrienols (αT3, γT3, and δT3), and α-tocopherol (αT) in human cervical carcinoma (HeLa) cells. Their mechanism(s) of action on cell cycle signaling pathway were also investigated. Results showed that the antiproliferative effect of αT3 (IC₅₀: 3.19 ± 0.05 µM) and γT3 (IC ₅₀: 2.85 ± 0.07 µM) was more potent than δT3 (IC ₅₀: >100 µM) and αT (IC₅₀: 69.46 ± 3.01 µM). Both αT3 and γT3 also demonstrated a dose-dependent and time-dependent induction of cell death.They caused cell cycle arrest at G2/M phase and triggered apoptosis as displayed by the externalization of annexin V—targeted phosphatidylserine and accumulation of sub-G1 peak. At a concentration of 3 µM, αT3 downregulated the expression of cyclin D3, p16, and CDK6, while having no effect on cyclin D1, p15, p21, p27, and CDK4 expression. However, γT3 showed no effect on these proteins. The induction of HeLa cell apoptosis by αT3 and γT3 appeared to be associated with the expression of IL-6, but not the other cytokines (IFN-γ, IL-2, and IL-10).Taken together, the results suggest that αT3 and γT3 are more effective than δT3 and αT in inhibiting HeLa cell proliferation, and their mode of action could be through the upregulation of IL-6, and the downregulation of cyclin D3, p16, and CDK6 expression in the cell cycle signaling pathway.

The chloroform extract of Physalis minima produced a significant growth inhibition against human T-47D breast carcinoma cells as compared with other extracts with an EC₅₀ value of 3.8 µg/mL. An analysis of cell death mechanisms indicated that the extract elicited an apoptotic cell death. mRNA expression analysis revealed the coregulation of apoptotic genes, that is, c-myc , p53, and caspase-3. The c-myc was significantly induced by the chloroform extract at the earlier phase of treatment, followed by p53 and caspase-3. Biochemical assay and ultrastructural observation displayed typical apoptotic features in the treated cells, including DNA fragmentation, blebbing and convolution of cell membrane, clumping and margination of chromatin, and production of membrane-bound apoptotic bodies. The presence of different stages of apoptotic cell death and phosphatidylserine externalization were further reconfirmed by annexin V and propidium iodide staining. Thus, the results from this study strongly suggest that the chloroform extract of P minima induced apoptotic cell death via p53-, caspase-3 -, and c-myc-dependent pathways.

There is an increasing body of data showing that activated cancer therapy—the synergistic effect of “preloaded” molecules and a tuned energy source to produce cytopathogenic moieties—is a promising new modality for cancer treatment.The key activated therapies are photodynamic therapy (PDT), which involves the synergy between light and photosensitizer molecules, and ultrasound activated therapy (USAT; also referred to as sonodynamic therapy), which involves the synergy between ultrasound and sonosensitizer molecules. PDT is a well-known activated therapy with roots dating back to 1900. However, minimal data exist on USAT. One reason is the lack of suitable sonosensitizers for clinical USAT use. The authors present both LC₅₀ toxicity and cancer cell cytotoxicity studies on 2 dual activation agents. These compounds function as both sonosensitizers and photosensitizers, and are referred to as SonneLux agents, designated SF1 and SF2. The sensitizers are derived from chlorophyll and are metal centered porphyrins known to specifically accumulate in hyperproliferating tissue. LC₅₀ studies on both SF1 and SF2 as determined in zebra fish reveal that both are essentially nontoxic to zebra fish. In the worst case, 5% zebra fish death is noted at the maximum soluble concentration of the sensitizer. In the cytotoxicity studies, melanoma cell line WM-266-4, derived from a metastatic site of a malignant melanoma, was tested against SF1 and SF2. Both sensitizer systems showed marked efficacy in the destruction of the implanted melanoma cells. They show great promise for clinical use in the future.

The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for chemoprevention against colon polyp formation. A total of 60 C57bl/6 mice were divided into 3 groups based on diet. One group received a low-fat, rodent chow diet (AIN76A). The second group received a high-fat “Western-style” diet (HFWD). The third group was fed the same HFWD with the mineral-rich extract included as a dietary supplement. Mice were maintained on the respective diets for 15 months. Autopsies were performed at the time of death or at the completion of the study. To summarize, the cumulative mortality rate was higher in mice on the HFWD during the 15-month period (55%) than in mice from the low-fat diet or the extract-supplemented high-fat diet groups (20% and 30%, respectively; P < .05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other 2 groups (P < .05). In addition to the grossly visible polyps, areas of hyperplasia in the colonic mucosa and inflammatory foci throughout the gastrointestinal tract were observed histologically in animals on the high-fat diet. Both were significantly reduced in animals on the low-fat diet and animals on the extract-supplemented HFWD.These data suggest that the mineral-rich algae extract may provide a novel approach to chemoprevention in the colon.

There is no established protocol proven to be beneficial for treatment of hepatocellular carcinoma recurrence after liver transplantation. Only a few reports have shown direct treatment by surgery or ablation to be independent predictors of survival for localized recurrence. Moreover, the necessity of immunosuppression to prevent allograft rejection makes many physicians hesitate to administer systemic chemotherapy. This case report documents a case in which the administration of an herbal product, an extract of the lacquer tree, Rhus verniciflua Stokes, was associated with a decrease in the size of lung metastases in a patient with recurrent hepatocellular carcinoma after liver transplantation refractory to doxorubicin. This patient experienced prolonged survival compared with average survival times and little toxicity.

Today, more than ever before, millions of people are seeking an approach to medicine and health care that is more comprehensive, more holistic and integrative, and more compassionate and sensitive to their needs as a whole person. This is particularly true for those dealing with cancer. Changing patient demographics, heightened consumer demand for complementary and alternative medicine (CAM) products and services, advances in medical science and technology, expanding access to the Internet and health information, and other factors have contributed to a wave of transformation that is unprecedented in its impact on the entire health care system. These trends have fueled the emerging fields of integrative medicine and oncology, which are growing rapidly. As these fields continue to evolve, they will move beyond the present integrative model to a broader vision of whole-person, multidimensional care that will more fully and coherently address and embrace all dimensions of the human experience. This article describes 6 major driving forces behind the wave of transformation presently under way in medicine and health care. It provides a brief, historical overview of integrative medicine and oncology and summarizes the present status of these emerging fields. It discusses the future of integrative medicine and oncology, including a multidimensional approach to care, and highlights 5 key elements that underlie this approach. Finally, it describes The Seven Levels of Healing— a model of multidimensional care—and concludes with a discussion of 3 important challenges and opportunities for medicine and health care that lie on the horizon.