This cheap oral drug significantly enhances the effect of cancer radiotherapy

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This cheap oral drug significantly enhances the effect of cancer radiotherapy

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Science Sub-Journal: This cheap oral drug significantly enhances the effect of cancer radiotherapy. 

Advanced tumors often have brain metastases (BM). Once brain metastases occur, the patient’s quality of life will linearly decrease. Radiotherapy can currently alleviate the progression of brain metastases.

Adding radiosensitizers may further improve tumor control. However, the blood-brain barrier (BBB) ​​is a major pharmacological challenge.

The blood-brain barrier refers to the barrier between blood plasma and brain cells formed by brain capillary walls and glial cells, and the barrier between plasma and cerebrospinal fluid formed by the choroid plexus, allowing only specific types of molecules to enter from the bloodstream Brain neurons and other surrounding cells.

The existence of the blood-brain barrier is of great significance in preventing harmful substances from entering the brain from the blood.

However, the blood-brain barrier also prevents the transfer of most small molecule drugs and macromolecules (such as peptides, proteins and nucleic acid drugs), which severely limits Treatment of central nervous system diseases (such as neurodegenerative diseases, brain tumors, brain infections and strokes, etc.).

Arginine, also known as L-arginine, is inexpensive and safe, and it passes through the blood-brain barrier relatively easily.

L-arginine is the endogenous substrate of nitric oxide synthase (NOS). Taking L-arginine can promote the production of nitric oxide (NO) at a therapeutic level.

Relatively high concentrations of NO can induce chemotherapy and Radiation sensitization. Therefore, the addition of arginine, the precursor of NO, to promote NO production may be beneficial to patients.

Recently, a research team from Cornell University and University College London has published a research paper titled: The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases in Science Advances, a sub-Journal of Science.

The study is a proof-of-concept randomized clinical trial that reports the results of oral arginine given before standard radiotherapy for 31 patients with brain metastases.

During the four-year follow-up period, 78% of patients with brain tumors who received arginine had a complete or partial response, while only 22% of patients who received a placebo responded.

The mechanism of arginine radiosensitization is mediated by nitric oxide, which ultimately damages the repair of DNA damage caused by the radiation of cancer cells, and at the same time greatly protects tumor infiltrating lymphocytes.

The research team first evaluated the expression of nitric oxide synthase (NOS) subtypes associated with tumors.

According to reports, inducible NOS2 is expressed in lung cancer and breast cancer cancer cells and tumor microenvironment (TME) cells, while the expression of NOS3 is limited to tumor-associated endothelial cells.

In a cohort of 42 BM patients with solid tumors, the research team detected NOS3/2 expression in the tumors.

Then, the research team observed that the patient’s tumor blood volume decreased significantly after taking L-arginine for 1 hour. This is a good phenomenon, indicating that arginine does play a role.

They speculated that this might be because tumor metabolism was affected, so they measured the tumor lactic acid concentration by magnetic resonance spectroscopy (MRS) and found that L-arginine reduced the tumor lactic acid content in patients with brain metastases.

With these findings in mind, the research team conducted a proof-of-concept randomized clinical trial to determine whether L-arginine would increase the efficacy of radiotherapy for cancer patients with unresectable brain metastases.

They recruited 63 patients who were randomized to receive oral L-arginine or placebo 1 hour before each radiotherapy.

The overall response rates of the placebo group and the L-arginine group were 22% and 77.4%, respectively, and the symptom relief rates were 50% and 93.5%, respectively.

Patients receiving L-arginine have a more complete neurological response. The median overall progression-free survival of the placebo group and L-arginine group were 2 months and 5 months, respectively.

Most patients in the L-arginine group who died during the study died because the cancer spread to other parts of the body.

Overall, these results indicate that oral administration of L-arginine to induce radiosensitization in patients with brain metastases is a feasible and effective strategy.

In a mouse model of triple-negative breast cancer (TNBC), the research team observed that L-arginine inhibited tumor metabolism, and this inhibition occurred in a NOS2-dependent manner.

At the molecular level, the transient metabolic inhibition of L-arginine may not be enough to cause cell death, but it significantly impairs the ability of cancer cells to repair DNA damage, indicating the radiosensitization effect of L-arginine observed in patients It is mainly induced in the internal way of cancer cells.

In summary, the study found that the administration of L-arginine directly affects the metabolism of cancer cells and affects the ability of cancer cells to survive sublethal DNA damage.

Any tumor that overproduces nitric oxide synthase is susceptible to the benefits of L-arginine treatment, so this mechanism can be used to sensitize the response of patients with brain metastases to radiation therapy.

Original link:

https://www.science.org/doi/10.1126/sciadv.abg1964

This cheap oral drug significantly enhances the effect of cancer radiotherapy

(source:internet, reference only)

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