Treatment with arginine, one of the amino-acid building blocks of proteins, enhanced the effectiveness of radiation therapy in cancer patients with brain metastases, in a proof-of-concept, randomized clinical trial from investigators at Weill Cornell Medicine and Angel H. Roffo Cancer Institute.
The study, published Nov. 5 in Science Advances, reported the results of administering arginine, which can be delivered in oral form, prior to standard radiation therapy in 31 patients who had brain metastases. Nearly 78 percent had a complete or partial response in their brain tumors over the follow-up period of up to four years, while only 22 percent of the 32 patients who received a placebo prior to radiotherapy had such a response.
The trial was designed to gauge the effectiveness of arginine as a “radiosensitizer” that enhances the effects of radiation treatment. However, the results, and arginine’s apparent mechanism of action, suggest that the amino acid might be useful more broadly as an anticancer therapy.
“Based on these findings we should continue to investigate arginine in combination with radiotherapy but also in combination with chemotherapy or immunotherapy, and even arginine on its own,” said senior author Dr. Leandro Cerchietti, an associate professor of medicine in the Division of Hematology and Medical Oncology, who participated in designing and implementing the trial at Angel H. Roffo Cancer Institute in Argentina where he was an attending oncologist. The trial was co-led by Dr. Alfredo Navigante at the Roffo Cancer Institute.
Arginine, also called L-arginine, is inexpensive and widely available, generally considered safe, and can get relatively easily from the bloodstream into the brain. The idea of using it to treat cancer arose from observations that tumors often aid their own survival by producing high levels of the related molecule nitric oxide (NO). The latter regulates multiple processes in the body including the flow of blood through blood vessels, and tumors cells often make more NO by upregulating their production of special enzymes called NO synthases, which synthesize NO from arginine.
Reducing NO production is one possible way of exploiting tumors’ dependence on this molecule, but hasn’t worked well, in part because of adverse side effects. The investigators hypothesized that boosting NO production instead-;by adding its precursor arginine-;might be beneficial, because while tumors can use NO to aid their growth and survival, they must keep its production below certain limits.
“Nitric oxide is a reactive molecule that on its own, or through other reactive molecules derived from it, can stress and damage a cell, so a cell can tolerate only so much of it.”
Dr. Rossella Marullo, study lead author, instructor in medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine