Vitamin C and Angiogenesis: New Research and New Mechanisms

By Dr. Joseph Casciari

One of the keys to the growth and spread of solid tumors is a process of new blood vessel growth called “angiogenesis.” In tumor angiogenesis, tumor cells produce growth factors that stimulate endothelial cells (blood vessel cells) to grow and migrate toward the tumor. This process is what provides tumors with the nutrients necessary to grow beyond microscopic sizes; it also provides an avenue for metastasis, the spread of tumor cells from the primary tumor to distant sites.

Since cancer patients tend to be depleted of vitamin C, administration of it tends to improve their overall “well being.”

Since Dr. Judah Folkman first described tumor angiogenesis roughly 30 years ago, there has been considerable interest in the possibility of curing cancer by halting tumor angiogenesis. The Bio-Communications Research Institute has also been studying angiogenesis and looking for natural products and nutrients that may inhibit it.

The process of tumor angiogenesis works as follows: Tumors produce a growth factor called “vascular endothelial growth factor,” or VEGF, which stimulates mature endothelial cells and recruits endothelial stem cells o the site of the tumor. These endothelial cells start proliferating in response to the growth factor; moreover, they secrete chemicals (proteinases, or MMPs)that break down extracellular matrix so that they can migrate toward the tumor. As tumor cells gain nutrients from a new vascular supply, their population growth increases VEGF production, leading to a “positive feedback” effect of increased angiogenesis. Tumor angiogenesis is complicated by the ability of tumor cells to produce angiostatin and endostatin. These act systemically to inhibit angiogenesis at metastasis sites. When a primary tumor is removed via surgery, angiostatin and endostatin production decrease, which in turn allows the metastatic nodules to suddenly become vascularized and grow. Angiostatin and endostatin are currently in clinical trials, though they are difficult and expensive to produce in large quantities.

Strategies to inhibit angiogenesis involve blocking VEGF, inhibiting endothelial cell proliferation, interfering with MMP activity, or preventing endothelial cell migration. For example, the VEGF blocker, Avastin, has been approved by the FDA for cancer treatment, while thalidomide (yes, the one that caused birth defectsinchildrenduringthe1960’s)is in clinical trials for cancer treatment because it interferes with endothelial cell migration. Other agents being tested include components isolated from shark cartilage. Because of the side effects associated with drugs of this sort, the search for natural angiogenesis inhibitors continues. The Bio-Communications Research Institute has recently gained evidence that vitamin C (ascorbate) at high concentrations can inhibit angiogenesis.

The Center’s interest in high dose, intravenously administered, vitamin C began with the ideas of Dr. Linus Pauling and continued with observations, in our laboratories and elsewhere, that at sufficient concentrations vitamin C is selectively toxic toward tumor cells. The Bio-Communications Research Institute’s research has shown that if vitamin C is administered by intravenous drip (oral administration is not sufficient), plasma concentrations high enough to selectively kill tumor cells can be achieved. Other nutrients, such as alpha-lipoic acid, can enhance the anti-cancer efficacy of vitamin C. Studies in guinea pigs have shown that high intra-tumor ascorbate concentrations can be achieved, and that tumor growth decreases significantly as the intra-tumor ascorbate concentration increases.

Concurrent to this research, Center physicians have been treating cancer patients with what we now refer to as “The Riordan Protocol” (after Dr. Hugh Riordan, The Center’s founder and vitamin C advocate). This involves a slow drip (over roughly one hour) of ten to 30 grams ascorbate diluted in one liter of Ringer’s solution. Treatments can be administered two or three times a week (an initial work-up and screening is required). Plasma vitamin C levels are monitored during the drip, and the dose can be gradually increased as needed. We have had several published positive case studies, particularly with metastatic renal cancer, pancreatic cancer, and breast cancer. Since cancer patients tend to be depleted of vitamin C, administration of it tends to improve their overall “well being.” Phase I clinical trials with intravenous vitamin C show that it is relatively safe; blood cell counts remained stable during treatment, as did blood chemistry parameters related to renal function. Phase II trials are underway at several medical research centers around the country. A protocol, with background and references, is available from The Center by request.

In the meantime, researchers at The Center have been examining vitamin C’s potentially beneficial biological effects. For instance, we have published information showing that the vitamin boosts cell mediated immune cell function. Recently, Dr. Nina Mikirova and others published a paper demonstrating that vitamin C, at concentrations relevant to intravenous infusions, inhibits endothelial cell migration and angiogenesis. To establish this, the researchers studied both mature endothelial cells and endothelial stem cells. Both of these cell types are capable of forming vessel like “tubules” under certain laboratory conditions. This tubule formation can be quantified; measurements indicate that endothelial cells exposed to high concentrations of vitamin C do not form tubules as readily as controls. Vitamin C does not impair endothelial cell metabolism or compromise viability, but it does interfere with migration. This is easy to measure: a plastic scraper is used to score a section of a Petri dish containing endothelial cells. Under normal conditions, but not in the presence of high vitamin C concentrations, the cells will migrate to close the gap. Vitamin C also inhibits the ability of endothelial cells to produce nitric oxide (a key regulator of angiogenesis) and VE-cahedrin (a “grappling hook” molecule that allows endothelial cells to move through tissue).

The discovery of vitamin C’s potential role in preventing tumor angiogenesis is exciting in light of the fact that this vitamin is already being administered intravenously to cancer patients. As a naturally occurring vitamin, its side effects are less severe than those of chemotherapeutic agents and may even provide “side benefits” such as improved overall health. It is a key part of The Center’s paradigm for cancer treatment to work with the body rather than against it and to focus on biological response modifiers that restore health by restoring balance and boosting the body’s own healing power.