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Arginine Treatment Enhances Effectiveness of Radiation Therapy for Cancer

Overloading a tumour that produces high levels of nitric oxide with more nitric oxide using arginine could weaken the tumour’s ability to repair DNA damage, effectively killing it.

A proof-of-concept, randomised clinical trial by investigators at Weill Cornell Medicine and Angel H. Roffo Cancer Institute has found that treatment with arginine, one of the amino-acid building blocks of proteins, can enhance the effectiveness of radiation therapy in cancer patients with brain metastases.

Nearly 78 per cent of the 31 patients who had brain metastases and was orally administered arginine prior to standard radiation therapy, experienced complete or partial response in their brain tumours over the follow-up period of up to four years. Meanwhile, only 22 per cent of the 32 patients who received a placebo prior to radiotherapy exhibited the same response. Although the trial was designed to gauge the effectiveness of arginine as a radiosensitiser that enhances the effects of radiation treatment, the results of the study suggested that arginine’s apparent mechanism of action may be broadly applied 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 is safe, inexpensive, widely available, and can be transported relatively easily from the bloodstream into the brain. The idea of using it to treat cancer arose from observations that tumours often aid their own survival by producing high levels of nitric oxide (NO) which regulates multiple processes in the body including blood flow. Tumour cells often produce more NO by upregulating the production of NO synthases, which synthesise NO from arginine.

As part of antitumour treatments, researchers have attempted to reduce NO production, but this has resulted in adverse side effects. In the current study, the researchers tried to increase NO production by adding arginine instead. Although tumours use NO to promote growth and survival, they must keep its production below certain limits. Therefore, they hypothesised that boosting the production of NO using arginine may be beneficial.

“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 study lead author Dr. Rossella Marullo, an instructor in medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine.

Dr. Marullo further added that overloading a high-NO tumour with much more NO prior to the radiation treatment could weaken the tumour’s ability to repair radiation-induced DNA damage. Through preclinical experiments in mice, this effect was confirmed to be true.

In the clinical trial, patients were treated with a high dose of arginine or placebo oral suspensions one hour before radiotherapy for their brain metastases. Six months after their courses of radiotherapy, 82 per cent of the group administered with arginine exhibited improvements or no worsening of neurological symptoms, compared to the 20 per cent in the placebo group. Although metastatic cancers usually have poor prognoses, there were some arginine-treated patients whose tumours in and outside the brain disappeared, suggesting the possibility of cures. As for arginine-treated patients who died during the study, most were due to their cancers metastasising elsewhere in the body.

According to Dr. Cerchietti, evidence from this study and prior study point to the possibility that arginine can not only directly hobble tumour cells but also boost the activity of antitumour immune cells. With these promising findings, the team plans to further their studies of arginine as an anticancer treatment on its own, or in combination with other therapeutics.

“In principle, any tumour that overexpresses NO-producing enzymes would be vulnerable to arginine treatment—and such tumours are very common,” said Dr. Cerchietti, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. Nevertheless, he warned that further studies are still 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. [APBN]

Source: Marullo et al. (2021). The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases. Science Advances, 7(45).