Arginine May Enhance Effectiveness of Radiation Therapy for Brain Metastases

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Treatment with arginine, an amino acid, enhanced the effectiveness of radiation therapy in patients with cancer and brain metastases in a proof-of-concept, randomized clinical trial published by Marullo et al in Science Advances.

The recently published paper 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% had a complete or partial response in their brain tumors over the follow-up period of up to 4 years, while only 22% 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 study author Leandro Cerchietti, MD, Associate Professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine, who participated in designing and implementing the trial at the Angel H. Roffo Cancer Institute in Argentina where he was an attending oncologist.

Arginine as a Potential Anticancer Agent

Arginine, also called L-arginine, is inexpensive and widely available, generally considered safe, and can travel 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.

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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,” said lead study author Rossella Marullo, MD, PhD, an instructor in medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine.

Overloading a high-NO tumor with much more NO prior to radiation treatment could weaken the tumor’s ability to repair radiation-induced DNA damage, she added—and indeed her preclinical experiments in mice confirmed this effect.

More Trial Findings

In the clinical trial, patients were treated with high-dose arginine or placebo oral suspensions an hour before radiotherapy for their brain metastases.

Six months after their courses of radiotherapy, 82% of the arginine group had improvement, or at least no worsening, of their neurologic symptoms, compared with 20% in the placebo group. Most of the arginine-treated patients who died during the study did so because of their cancers’ spread elsewhere in the body.

Moreover, although metastatic cancer usually has a dire prognosis, there were some arginine-treated patients whose tumors in and outside the brain disappeared.

Evidence from this study and prior research also suggests that arginine can not only directly hobble tumor cells but also boost the activity of antitumor immune cells, Dr. Cerchietti said.

The results have prompted the team to start and plan further studies of arginine on its own or in combination with other anticancer treatments.

“In principle, any tumor that overexpresses NO-producing enzymes would be vulnerable to arginine treatment—and such tumors are very common,” said Dr. Cerchietti. He cautioned that further studies are needed and patients should consult their doctor about the use of any supplements outside of a clinical trial. The doses of arginine used in this study are available in formulations that can be only obtained at a medical facility.

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