Abstract

BACKGROUND: Angiogenesis is critical to tumor growth and is therefore a potential target for cancer therapy. As many current inhibitors of angiogenesis exhibit host toxicity, natural alternatives are needed. At millimolar concentrations, ascorbate (vitamin C) inhibits migration and tubule formation by mature endothelial cells and endothelial progenitors. In the present study, we examined the effects of ascorbate, at levels relevant during intravenous infusion therapy, on angiogenesis using an ex vivo an in vivo assay.

METHODS: Two assays were used to evaluate effect of high-doses ascorbic acid on angiogenesis: ex vivo rat aortic ring explant assay in Matrigel matrices and in vivo Matrigel plug assay. In aortic rings, we quantified microvessel growth, branching and vessel regression under different treatment conditions. In murine angiogenesis assay, male C57 mice 6-8 weeks old were treated by high-dose ascorbic acid and the number of microvessels was analyzed by histological method. To characterize the population of cells that formed capillary network and microvessels, the sections were stained by CD34 and CD31 antibodies.

RESULTS: Results show that sprouting of endothelial tubules from aortic rings was reduced in a concentration-dependent fashion by ascorbate: while controls roughly tripled sprout densities during the study, ascorbate (1 mg/mL, 5.5 mM) actually reduced sprout density. In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plug was diminished if the mice were treated with 430 mg/kg vitamin C: numbers of vessels, and vessel densities, in plugs from treated mice were roughly 30% less than those in plugs from untreated mice.

CONCLUSIONS: We conclude that the inhibition of angiogenesis by ascorbate suggested in vitro is confirmed in vivo, and that angiogenesis inhibition may be one mechanism by which intravenous ascorbate therapy shows efficacy in animal experiments and clinical case studies.

Clin Cancer Res. 2010 Jan 15;16(2):509-20. Epub 2010 Jan 12.

Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.

Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ.

Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.

Abstract

PURPOSE: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%.

EXPERIMENTAL DESIGN: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks.

RESULTS: There was a time- and dose-dependent increase in measured H(2)O(2) production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H(2)O(2). Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival.

CONCLUSIONS: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer.

AND

In Vivo. 2010 May-Jun;24(3):249-55.

Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer.

Pollard HB, Levine MA, Eidelman O, Pollard M.

Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, USUHS, Bethesda, MD 20814, USA. hpollard@usuhs.mil

Abstract

AIM: The aim of this study was to test for the influence of ascorbic acid on tumorigenicity and metastases of implanted PAIII prostate cancer adenocarcinoma cells in syngeneic LW rats.

MATERIALS AND METHODS: Hormone-refractory prostate cancer PAIII cells were implanted subcutaneously into immunologically intact, Lobund-Wistar (LW) rats. Intraperitoneal pharmacological doses of ascorbic acid were administered each day for the ensuing 30 days. On the 40th day, animals were sacrificed. Local tumor weights were measured, and metastases were counted.

RESULTS: At the end of the 40 day experimental period, the primary tumors were found to be significantly reduced in weight (p=0.026). In addition, sub-pleural lung metastases were even more profoundly reduced in number and size (p=0.009). Grossly enlarged ipsilateral lymph node metastases declined from 7 of 15 rats to 1 of 15 rats.

CONCLUSION: Pharmacological doses of ascorbic acid suppress tumor growth and metastases in hormone-refractory prostate cancer.

And

CMAJ. 2006 Mar 28;174(7):937-42.

Intravenously administered vitamin C as cancer therapy: three cases.

Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M.

Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md 20892-1372, USA.

Abstract

Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 micromol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50-100 g) given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.

AND  we now know it is best to use this initially:

Ann Oncol. 2008 Nov;19(11):1969-74. Epub 2008 Jun 9.

Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.

Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr.

Montreal Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, McGill University and the Jewish General Hospital, Montreal, Quebec, Canada. l.hoffer@mcgill.ca

Abstract

BACKGROUND: Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies.

PATIENTS AND METHODS: Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5 g ascorbic acid/kg body weight three times weekly.

RESULTS: Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response.

CONCLUSIONS: High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.

AND

Oncology (Williston Park). 2001 Oct;15(10):1349-54; discussion 1357-60.

The role of amifostine as a radioprotector.

Wasserman TH, Brizel DM.

Department of Radiation Oncology, Washington University Medical Center, St. Louis, Missouri 63110, USA.

Abstract

Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. Radiation doses that can be delivered, without causing severe damage to surrounding normal tissues, can be insufficient to eradicate a tumor. Agents have been developed to protect normal tissue from the toxicities of radiation. The aminothiol amifostine (Ethyol) is the subject of extensive research as a protector. Several studies have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. This article reviews the physicochemical basis of radiation therapy on biologic tissues and the mechanisms responsible for the protective effects of amifostine. The increasing body of biochemical, preclinical, and clinical data can justify the use of protectors such as amifostine with radiotherapy to provide improved therapeutic efficacy and quality of life for the patient. This article will review the current understanding of the nature of toxicity resulting from radiation therapy and the benefits that can be derived from using protection to increase the tolerance of normal tissue to radiation damage.

Integr Cancer Ther. 2005 Dec;4(4):329-51.

Commentary: the pharmacological antioxidant amifostine — implications of recent research for integrative cancer care.

Block KI, Gyllenhaal C.

Block Center for Integrative Cancer Care, Evanston, Illinois 60201, USA. drblock@blockmedical.com

Abstract

Amifostine is a pharmacological antioxidant used as a cytoprotectant in cancer chemotherapy and radiotherapy. It is thought to protect normal tissues relative to tumor tissue against oxidative damage inflicted by cancer therapies by becoming concentrated at higher levels in normal tissues. The degree to which amifostine nevertheless accumulates in tumors and protects them against cancer therapies has been debated. Guidelines have been published that direct its use in chemotherapy and radiation, taking into consideration the concerns of tumor protection. In this article, clinical studies of amifostine appearing since the publication of the most recent set of guidelines are reviewed. Randomized and nonrandomized trials of regimens involving chemo-therapeutic agents (chemotherapy, chemoradiation, conditioning regimens for bone marrow transplant) are discussed. Nineteen studies showed positive effects for amifostine reducing the level of side effects of these regimens, while 9 showed no effect and 1 had a questionable result. Clinically relevant levels of amifostine toxicity were observed in several studies, but subcutaneous administration may reduce such toxicity. Amifostine showed protection against mucositis, esophagitis, neuropathy, and other side effects, although protection against cisplatin-induced ototoxicity was not observed. No evidence of tumor protection was observed. Amifostine may enable populations unable to tolerate conventional cancer therapy to receive treatment of their cancers, even if some degree of tumor protection is eventually discovered. The authors discuss the implications of this research for patient populations seen in integrative cancer care centers and for research on phytochemical antioxidants such as vitamins and carotenoids.