In a proof of concept, randomized clinical trial, investigators from Weill Cornell Medicine & Angel H. Roffo Cancer Institute found that radiation therapy with arginine was more effective for brain cancer patients with brain metastases.
The Nov. 5 Science Advances study reported on the effects of administering oral arginine to 31 brain metastases patients. Nearly 78 per cent of brain tumor patients experienced a partial or complete response over a four-year follow-up. Only 22 percent of 32 patients who received a placebo before radiotherapy saw such a response.
This trial was intended to determine if arginine can be used as a radiosensitizer that increases radiation treatment's effectiveness. The results and the apparent mechanism of action suggest that arginine might be more useful as an anticancer treatment.
"Based on these findings, we should continue investigating arginine with radiotherapy, but also in combination chemotherapy or immunotherapy, and even arginine alone," stated senior author Dr. Leandro Cechietti, an associate professor of medicine at the Division of Hematology and Medical Oncology. He was also involved in the design and implementation of the trial at Angel H. Roffo Cancer Institute, Argentina. Dr. Alfredo Navigante, Roffo Cancer Institute, co-led the trial.
L-arginine (also known as Arginine) is cheap and readily available. It can also be absorbed into the brain relatively quickly from the bloodstream. It was discovered that cancer cells often produce high levels of the related chemical nitric oxide (NO) and this led to the idea of using it for treatment. This regulates many processes within the body, including blood flow through blood vessels. Tumor cells can produce more NO by increasing their production of NO synthases (enzymes that synthesize NO from arginaine).
Although reducing NO production may be one way to exploit tumors' dependence upon this molecule, it hasn't been successful due to adverse side effects. Researchers suggested that increasing NO production by adding its precursor, arginine, might be more beneficial. Tumors can use NO to help their growth and survival. However, it must not exceed certain levels.
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"Nitric Oxide is a reactive molecular that can damage or stress a cell, either by itself or through other reactive molecules derived form it," explained Dr. Rossella Marullo who is an instructor in medicine at Weill Cornell Medicine's Division of Hematology and Medical Oncology.
She said that overloading a tumor high in NO with more radiation could reduce the tumor's ability repair radiation-induced DNA damage. Her preclinical studies on mice have confirmed this effect.
Patients were given high-dose arginine and placebo oral suspensions one hour before radiotherapy was started for brain metastases. These are brain tumors that have spread from primary tumors, such as the lung, in the clinical trial.
Six months after receiving radiotherapy, 82 per cent of patients in the arginine treatment group experienced improvement or no worsening of their neurological symptoms compared to 20 percent in the placebo. The majority of patients treated with arginine who died in the course of the study were due to cancer spread elsewhere in their bodies.
Additionally, even though metastatic cancer is usually a fatal disease, some patients treated with arginine had tumors that disappeared from the brain. This suggests the possibility of finding a cure.
This study and previous research support the idea that arginine may not only be able to directly harm tumor cells but also increase anti-tumor immunity cells' activity, Dr. Cerchietti stated.
These promising results led the team to plan and start further research on arginine as an anticancer treatment or alone.
"In principle, any tumor that is overexpressed NO-producing enzymes would be susceptible to arginine treatment," Dr. Cerchietti said. He is also a member the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. However, he cautions that more research is needed and that patients should talk to their doctors about any supplementation. You can only obtain the arginine doses used in this study from a medical facility.
