Jeanne Drisko

Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice

Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy

Pharmacological use of ascorbate (vitamin C) enhanced chemosensitivity of ovarian cancer in preclinical models and reduced chemotherapy-associated toxicity in patients. Not-So-Sour Results for Cancer Patients Ascorbic acid, or vitamin C, was first proposed as a cancer treatment decades ago. Unfortunately, despite anecdotal evidence for effectiveness of intravenous ascorbate, initial clinical trials used the oral form of the drug. On the basis of the results from these trials, ascorbate was determined to be ineffective, and its use for cancer was largely abandoned outside of alternative medicine. However, accumulating anecdotal evidence once again led scientists to reconsider the therapeutic potential of this compound. Ma and colleagues investigated the use of intravenous ascorbic acid in conjunction with chemotherapy for ovarian cancer, starting from preclinical models and culminating in a human trial. The preclinical studies provided evidence of anticancer effects of ascorbate and demonstrated synergy with chemotherapeutic agents. The early-phase human trial was too small to statistically confirm efficacy, but it demonstrated a significant reduction in chemotherapy-induced adverse effects in patients receiving ascorbate. Although larger studies will be needed to confirm a direct anticancer effect of ascorbate, its ability to decrease chemotherapy-induced adverse effects should already make it a very valuable addition to chemotherapeutic regimens, because a reduction in toxicity would allow patients to tolerate higher (and potentially more effective) doses of chemotherapy. Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H2O2) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate–activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial

IMPORTANCE Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy. OBJECTIVE To determine if an EDTA-based chelation regimen reduces cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS Double-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial. INTERVENTIONS Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events. MAIN OUTCOME MEASURES The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036. RESULTS Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results. CONCLUSIONS AND RELEVANCE Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00044213.

The Use of Antioxidants with First-Line Chemotherapy in Two Cases of Ovarian Cancer

Objective: Because of poor overall survival in advanced ovarian malignancies, patients often turn to alternative therapies despite controversy surrounding their use. Currently, the majority of cancer patients combine some form of complementary and alternative medicine with conventional therapies. Of these therapies, antioxidants, added to chemotherapy, are a frequent choice. Methods: For this preliminary report, two patients with advanced epithelial ovarian cancer were studied. One patient had Stage IIIC papillary serous adenocarcinoma, and the other had Stage IIIC mixed papillary serous and seromucinous adenocarcinoma. Both patients were optimally cytoreduced prior to first-line carboplatinum/paclitaxel chemotherapy. Patient 2 had a delay in initiation of chemotherapy secondary to co-morbid conditions and had evidence for progression of disease prior to institution of therapy. Patient 1 began oral high-dose antioxidant therapy during her first month of therapy. This consisted of oral vitamin C, vitamin E, beta-carotene, coenzyme Q-10 and a multivitamin/mineral complex. In addition to the oral antioxidant therapy, patient 1 added parenteral ascorbic acid at a total dose of 60 grams given twice weekly at the end of her chemotherapy and prior to consolidation paclitaxel chemotherapy. Patient 2 added oral antioxidants just prior to beginning chemotherapy, including vitamin C, beta-carotene, vitamin E, coenzyme Q-10 and a multivitamin/mineral complex. Patient 2 received six cycles of paclitaxel/carboplatinum chemotherapy and refused consolidation chemotherapy despite radiographic evidence of persistent disease. Instead, she elected to add intravenous ascorbic acid at 60 grams twice weekly. Both patients gave written consent for the use of their records in this report. Results: Patient 1 had normalization of her CA-125 after the first cycle of chemotherapy and has remained normal, almost 3½ years after diagnosis. CT scans of the abdomen and pelvis remain without evidence of recurrence. Patient 2 had normalization of her CA-125 after the first cycle of chemotherapy. After her first round of chemotherapy, the patient was noted to have residual disease in the pelvis. She declined further chemotherapy and added intravenous ascorbic acid. There is no evidence for recurrent disease by physical examination, and her CA-125 has remained normal three years after diagnosis. Conclusion: Antioxidants, when added adjunctively, to first-line chemotherapy, may improve the efficacy of chemotherapy and may prove to be safe. A review of four common antioxidants follows. Because of the positive results found in these two patients, a randomized controlled trial is now underway at the University of Kansas Medical Center evaluating safety and efficacy of antioxidants when added to chemotherapy in newly diagnosed ovarian cancer.

Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H(2)O(2) derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cells underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.

The use of antioxidant therapies during chemotherapy

OBJECTIVE At the present time, many cancer patients combine some form of complementary and alternative medicine therapies with their conventional therapies. The most common choice of these therapies is the use of antioxidants. RESULTS A review of four common antioxidants is undertaken, which includes vitamin E (mixed tocopherols and tocotrienols), beta-carotene (natural mixed carotenoids), vitamin C (ascorbic acid), and vitamin A (retinoic acid). Antioxidants act as electron acceptors as well as therapeutic biologic response modifiers. Despite the fact that chemotherapy-induced formation of free radicals is well-demonstrated, chemotherapy-induced cytotoxicity in general does not seem to depend on formation of reactive oxygen species. CONCLUSIONS Currently, evidence is growing that antioxidants may provide some benefit when combined with certain types of chemotherapy. Because of the potential for positive benefits, a randomized controlled trial evaluating the safety and efficacy of adding antioxidants to chemotherapy in newly diagnosed ovarian cancer is underway at the University of Kansas Medical Center.

Effect of Yoga on Arrhythmia Burden, Anxiety, Depression, and Quality of Life in Paroxysmal Atrial Fibrillation: The YOGA My Heart Study

OBJECTIVES The purpose of this study was to examine the impact of yoga on atrial fibrillation (AF) burden, quality of life (QoL), depression, and anxiety scores. BACKGROUND Yoga is known to have significant benefit on cardiovascular health. The effect of yoga in reducing AF burden is unknown. METHODS This single-center, pre-post study enrolled patients with symptomatic paroxysmal AF with an initial 3-month noninterventional observation period followed by twice-weekly 60-min yoga training for next 3 months. AF episodes during the control and study periods as well as SF-36, Zung self-rated anxiety, and Zung self-rated depression scores at baseline, before, and after the study phase were assessed. RESULTS Yoga training reduced symptomatic AF episodes (3.8 ± 3 vs. 2.1 ± 2.6, p < 0.001), symptomatic non-AF episodes (2.9 ± 3.4 vs. 1.4 ± 2.0; p < 0.001), asymptomatic AF episodes (0.12 ± 0.44 vs. 0.04 ± 0.20; p < 0.001), and depression and anxiety (p < 0.001), and improved the QoL parameters of physical functioning, general health, vitality, social functioning, and mental health domains on SF-36 (p = 0.017, p < 0.001, p < 0.001, p = 0.019, and p < 0.001, respectively). There was significant decrease in heart rate, and systolic and diastolic blood pressure before and after yoga (p < 0.001). CONCLUSIONS In patients with paroxysmal AF, yoga improves symptoms, arrhythmia burden, heart rate, blood pressure, anxiety and depression scores, and several domains of QoL.

Treating Irritable Bowel Syndrome with a Food Elimination Diet Followed by Food Challenge and Probiotics

Objective: In Irritable Bowel Syndrome, the gut-associated immune system may be up-regulated resulting in immune complex production, low-grade inflammation, loss of Class I bacteria, and translocation of inflammatory mediators and macromolecules outside of the GI lumen. Since food intolerance may be one of the reasons for this upregulation, our goal was to investigate the role of food intolerance in IBS patients. Methods: In this open label pilot study, we enrolled 20 patients with IBS by Rome II criteria (15 women, ages 24–81) who had failed standard medical therapies in a tertiary care GI clinic. Baseline serum IgE and IgG food and mold panels, and comprehensive stool analysis (CSA) were performed. Breath-hydrogen testing and IBS Quality-of-Life (QOL) questionnaires were obtained. Patients underwent food elimination diets based on the results of food and mold panels followed by controlled food challenge. Probiotics were also introduced. Repeat testing was performed at 6-months. We followed up with this cohort at 1 year after trial completion to assess the reported intervention and for placebo effect. Results: Baseline abnormalities were identified on serum IgG food and mold panels in 100% of the study subjects with significant improvement after food elimination and rotation diet (p < 0.05). Significant improvements were seen in stool frequency (p < 0.05), pain (p < 0.05), and IBS-QOL scores (p < 0.0001). Imbalances of beneficial flora and dysbiotic flora were identified in 100% of subjects by CSA. There was a trend to improvement of beneficial flora after treatment but no change in dysbiotic flora. The 1-year follow up demonstrated significant continued adherence to the food rotation diet (4.00 ± 1.45), minimal symptomatic problems with IBS (4.00 ± 1.17), and perception of control over IBS (4.15 ± 1.23). The continued use of probiotics was considered less helpful (3.40 ± 1.60). Conclusion: These data demonstrate that identifying and appropriately addressing food sensitivity in IBS patients not previously responding to standard therapy results in a sustained clinical response and impacts on overall well being and quality of life in this challenging entity.

Evaluation of five probiotic products for label claims by DNA extraction and polymerase chain reaction analysis.

Label claims were evaluated for five probiotic products. Specific oligonucleotide primers were designed for 11 species from the Bifidobacterium, Lactobacillus, and Streptococcus genera. Polymerase chain reaction, gel electrophoresis, and amplicon excision with DNA sequencing were performed: Sequence analysis and DNA homology comparisons followed. Bifidobacterium bifidum was not detected in two of the five samples by PCR analysis. Also, Lactobacillus species were found in two of the five product samples for which the species was not listed as an ingredient. We conclude that (1) lack of B. bifidum in two probiotic products may be attributed to different preparation standards among probiotic manufacturers, and (2) indentification of additional Lactobacillus species may represent contamination of the samples due to manufacturers utilizing shared equipment to produce all probiotics.

Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy.

Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer.