RECNAC Cancer Research Update

By Joseph Casciari, Ph.D.

The RECNAC project marked its 8th anniversary in February with a Lunch and Lecture presentation at The Center. Dr. Hugh D. Riordan, RECNAC Project Director, began by stating the project’ s goals and introducing the RECNAC staff. RECNAC started in 1989 with the stated goal, contingent upon reaching funding targets, of learning why cancer develops and how to safely treat and prevent it.

Ascorbic acid (vitamin C) emerged from these studies as an especially promising agent …

Neil Riordan, RECNAC Project Manager, described the project’s history. The first two years of the RECNAC project were spent in an exhaustive literature review covering theories on cancer and current therapies. RECNAC has compiled a database of over 6000 cancer related articles.

The next phase involved screening hundreds of vitamin and nutrient combinations for their effects on cancer cells and normal cells incubated in tissue culture plates. Ascorbic acid (vitamin C) emerged as an especially promising agent, showing preferential toxicity toward tumor cells.

The RECNAC project has devoted considerable effort investigating the potential of “mega-dose” ascorbate therapy. A phase one clinical trial is being conducted at the University of Nebraska to insure that high doses of ascorbate are non-toxic to humans. Terminal cancer patients are being treated for eight weeks with continuous intravenous ascorbate infusion. Doses of up to fifty grams per day have been used, with no toxicity observed at that dose. One patient elected to continue therapy, and is reporting improved well being after ten months.

Dr. Joseph Casciari described a proposed mechanism of ascorbate toxicity to tumors based on its ability to convert oxygen and oxygen free radicals to hydrogen peroxide, which can damage cells unless it is broken down by the enzyme, catalase. Since tumor cells often contain low levels of catalase, they are more sensitive to hydrogen peroxide. Casciari has tested ascorbate efficacy using tumor cells grown inside hollow fibers. These hollow fiber tumors share important traits with solid tumors in patients, including the presence of cell sub-populations resistant to conventional therapies.

Casciari found hollow fiber tumors to be five to ten times more resistant to ascorbate than tumor cells grown in tissue culture plates. In a collaborative effort with the H. L. Snyder Memorial Research Foundation, hollow fiber tumors implanted under the skin of mice were found to be unaffected by ascorbate administered in the intraperitoneal cavity, suggesting that mice cleared ascorbate from their bodies before it could accumulate in sufficient quantities at the tumor site. Efforts are underway at RECNAC to overcome these problems by developing ways to recycle ascorbate and increase its delivery to tumors.

Paul Taylor described the Intravenous Ascorbate Inhibition Assay (IAIA). This assay was developed at RECNAC to determine, on a patient by patient basis, whether ascorbate doses given in therapy are sufficient for cytotoxic effect. In this protocol, tumor cells grown in tissue culture plates are exposed to patient serum drawn before or after ascorbate therapy. For some patients,serum collected prior to ascorbate therapy actually stimulated tumor cell growth. Post-therapy results vary among individual patients. Taylor showed IAIA data from two patients given 65 gram ascorbate infusions over an eight hour period. Serum from one patient killed the entire tumor cell population, while serum from another patient killed only a fraction of the tumor cells. Measurements of blood ascorbate concentrations after infusion indicated that three or more infusions may be required before blood ascorbate levels get high enough to kill tumor cells.

Vitamin C is not the only lead RECNAC scientists are pursuing. Another area of interest is tumor angiogenesis. This is the process whereby tumors induce new capillaries to grow toward the tumor. Angiogenesis provides tumors with the nutrients necessary for growth beyond microscopic sizes. RECNAC scientists hope to inhibit angiogenesis, thereby starving tumors at an early stage. Taking clues from traditional Chinese medicine, Dr. Xiao Long Meng, with the help of RECNAC scientists, Jan Ryel and Kashif Sheikh, is isolating extracts from herbs and natural products in hopes of finding new agents that inhibit angiogenesis and tumor growth.

Dr. Meng described a triage for screening extracts. First, extracts are tested against tumor cells and normal cells to identify those that are preferentially toxic to tumor cells. Then extracts are added to tumor cells implanted on chick embryo membranes. Without extracts, tumor cells grow on the membrane and induce angiogenesis. Extracts that slow tumor growth or inhibit angiogenesis are considered for further study. The most promising extracts are sent to Beijing, China, to be tested in a mouse melanoma tumor model. Two extracts inhibit mouse melanoma by fifty percent. One inhibits angiogenesis, and the other preferentially kills tumor cells.

Dr. Fei Fei Zhong and Tracey Schmidt are looking for ways to boost the body’s immune response to cancer. This effort initially focused on monocytes, the white blood cells responsible for immunity. However, it was serendipitously observed that blood platelets can, under certain conditions, be more toxic to tumor cells than monocytes. Dr. Zhong presented data suggesting that platelet toxicity depends on cofactors in the blood plasma, since they exhibit their toxic effect only when blood plasma is present. Thus, while monocyte studies continue, the potential role of platelets in combating cancer response is being examined.

Neil Riordan described research by Sergey Nesterishin to study electrical events in wound healing and regeneration in salamanders. These experiments employ the Faraday cage that RECNAC had built. We hope this research will increase our understanding of how cells transform from their resting state to one of rapid growth. Riordan also recognized the contributions of RECNAC Administrator, Kim Shoemaker, who helps keep the project running smoothly.

Finally, Neil Riordan shared a case study involving a terminal breast cancer patient with multiple bone metastases that he met during his physician assistant internship. The patient was bedridden, required morphine infusions for pain, and had severe blood clotting in both arms. She was given fifteen grams of intravenous vitamin C. The patient showed much improvement, and her vitamin C dose was increased to 100 grams per day. She was discharged two weeks later, and a subsequent bone scan showed some bone metastases had resolved. Although she died six months later after fracturing her hip, vitamin C therapy improved her quality of life tremendously in those final six months.

The RECNAC project is scheduled to continue until December 31, 1999.