Cancer is still one of the leading causes of death globally. According to the World Health Organization (WHO), it accounted for nearly 10 million deaths in 2020. Various cancer treatments, including surgery, radiation therapy, chemotherapy, immunotherapy, etc. have been developed.

Radiation therapy (RT) is a popular, essential and effective treatment that destroys or controls tumors. Radiation therapy kills cancer cells by inducing DNA damage and preventing the cells from dividing. It is a cancer treatment that uses high-energy ionizing radiation (X-rays, gamma rays) and particle therapy (carbon ions, electrons, neutrons, α-particles, β-particles, etc.) [1]. It is estimated that approximately 50% of cancer patients receive RT, while more than half of all patients (about 70%) require RT at some stage of treatment [2]. RT is part of first-line cancer treatment for more than 30% of patients combined with surgery, cytotoxic chemotherapy, and immunotherapy [3].

Ionizing radiation disrupts metabolism in cells and organs, causing radiation damage. The search for drugs that protect healthy tissues from ionizing radiation during the course of radiation therapy and nuclear incidents is therefore a primary goal in radiation oncology and radiobiology.

Radiomodifiers can be divided into (a) radioprotectors (compounds designed to protect healthy tissues and molecules from both direct and indirect damage caused by ionizing radiation) or (b) radiomitigators (reduce and help repair damage), depending on whether they are administered before or after irradiation, respectively. Development of such compounds is an urgent task, since no ideal drug has been created so far. Amifostine, which is currently the only approved clinical radioprotector, has a number of side effects such as nausea, vomiting, and hypotension [4]. Ionizing radiation damages tissues primarily by generating free radicals. Thus, such compounds are designed to create substances that neutralize free radicals.

RADIOPROTECTORS: CLASSIFICATION AND MECHANISMS OF ACTION

The main mechanisms of action of radioprotectors include

a) scavenging of free radicals (by suppressing their formation or detoxification of radiation-induced free radicals),
b) inducing local hypoxia by preventing synthesis of reactive oxygen species (ROS),
c) boosting antioxidant protection such as GSH (reduced glutathione), antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPX), thioreductase, catalase (CAT), etc.,
d) activation of DNA repair pathways,
e) slowing cell division or inhibition of apoptosis,
f) modulation of redox-sensitive genes,
g) modulation of growth factor and cytokine production,
h) control of the inflammatory responses,
i) chelation or decorporation of radionuclides.

The primary classes of radioprotectors include thiol-containing molecules, cyclic nitroxides, antibiotics, phytochemicals (plant extracts, polyphenolic compounds, non-polyphenolic compounds), vitamins, oligoelements, mimetics of superoxide dismutase (SOD) and nanoparticles, hormones and hormone mimetics.

Thiol-containing molecules such as cysteine, N-acetylcysteine, cysteamine, and cystamine have shown promise for eliminating side effects caused by radiation therapy. Amifostine, which is also a thiol-containing molecule, is the only radioprotector used in clinical practice, though its use is limited due to its high toxicity. The main mechanism of action is the scavenging absorption of free radicals that occur when exposed to ionizing radiation [4].

Natural polyphenolic compounds offer significant radioprotection by scavenging free radicals and boosting antioxidant defense systems [5]. These compounds are shown in tab. 1. Nevertheless, none of the many polyphenols tested to date provides truly effective radioprotection [6], since compounds of this class have limited water solubility and undergo metabolism to form glucuronides, sulfates, and methyl derivatives. Only a small percentage of free polyphenols can be detected in blood, whereas their metabolites are generally less potent antioxidants than their parent compounds [7].

Vitamin A and beta-carotene have demonstrated radioprotective properties (reduced mortality) in mice exposed to partial or total radiation [8]. Oral pretreatment with ascorbic acid prevented gastrointestinal syndrome in mice receiving a lethal dose of radiation. [9]. Subcutaneous administration of vitamin E (alpha-tocopherol) 1 hour before or 15 minutes after irradiation (60Co, 0.2 Gy/min) significantly increased the 30-day survival after irradiation in CD2F mice [10]. α-Lipoic acid was also an antioxidant and a free radical scavenger.

Many endogenous protective enzymes such as superoxide dismutase (SOD) and metalloproteins contain trace elements. These enzymes are critical for neutralizing Reactive Oxygen Species induced by radiation. Zinc, copper, manganese, and selenium are essential trace elements that protect DNA against radiation-induced damage [11]. Superoxide dismutase has also acted as a radioprotector. Preliminary studies have shown that treatment of mice with bovine SOD IV resulted in the recovery of erythrocytes, reticulocytes, and leukocytes after exposure to X-rays [12].

It has been shown that some hormones and their analogues can function as effective radioprotective agents. Melatonin (N-acetyl-5-methoxytryptamine) protects DNA, lipids, and proteins from oxidative damage by scavenging free radicals. In vitro and in vivo studies with different species demonstrated that exogenous melatonin reduced oxidative stress and inflammation resulting from ionizing radiation [13]. Indralin, an alpha-adrenomimetic, has demonstrated clear radioprotective effects for the skin, some organs, and cellular DNA in various species of animals exposed to radiation [14].

Some antibiotics also exhibit radioprotective properties. More recently, high-throughput screening has identified tetracyclines and fluoroquinolones as potential radioprotectors and mitigators of hematopoietic syndrome [15]. It is important to note that antibiotics as radioprotectors have not yet passed clinical trials. Moreover, their side effects at potentially radioprotective doses may represent a limiting factor for their efficacy.

It should be noted that adenosine receptor agonists have also been investigated as radioprotectors. Experiments have shown that pre-radiation administration of AMP and dipyridamole has a positive effect on hematopoiesis and improves survival [16, 17]. Later, it was discovered that adenosine A3 receptor agonist (N6-(3-iodobenzyl)adenosine-5’-N-methyluronamide (IB-MECA)) acts as a homeostatic regulator of bone marrow hematopoiesis [18].

RADIOMITIGATORS: CLASSIFICATION AND MECHANISMS OF ACTION

Radiomitigators are compounds administered during or immediately following radiation therapy or exposure to reduce damage to normal tissues before symptoms appear (tab. 2). Radiomitigators minimize toxicity even after radiation has been delivered, which distinguishes them from radioprotectors (which reduce direct radiation damage to healthy tissues).

Currently, all FDA-approved anti-radiation agents (filgrastim, a recombinant DNA form of natural G-CSF; pegfilgrastim, a pegylated form of recombinant human G-CSF; sargramostim, recombinant GM–CSF) are classified as radiomitigators. The properties of L-glutamine, probiotics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins, somatostatin analogues, various immunomodulators, nonsteroidal anti-inflammatory compounds, etc. were studied additionally [14].

Cytokines such as filgrastim, sargramostim, and interleukins (IL-1, IL-12) accelerate bone marrow recovery. Their main mechanism of action is to stimulate hematopoiesis [19]. In addition, antibiotics and antifungal drugs are used to treat infections in patients with neutropenia.

Pro-inflammatory cytokines and growth factors, notably TGF-β, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), are central drivers of radiation-induced fibrosis. TGF-β can induce production of reactive oxygen species (ROS) and nitric oxide (NO). It is essential in the initiation and progression of chronic oxidative damage after high-dose radiation exposure. Combined inhibition of TGF-β and PDGF signaling pathways reduces radiation-induced pulmonary fibrosis, lowering pneumonitis and increasing survival [20].

Ionizing radiation induces the activity of COX-2, which is associated with ROS production and activation of inflammation. Therefore, radioprotective properties of the drugs that inhibit this enzyme have been studied. Meloxicam given to mice before or repeatedly after a sublethal irradiation enhanced the recovery of hematopoiesis progenitor cells committed to granulocyte-macrophage and erythroid development. However, the increase in survival was only observed when meloxicam was applied before irradiation [21].

Probiotics are live microorganisms found in food that provide health benefits by strengthening the intestinal barrier. Preparations containing Bifidobacterium, Lactobacillus, and Streptococcus strains mitigated acute gastrointestinal syndrome after radiation exposure by reducing the severity and incidence of diarrhea [22]. In addition, prebiotics promote the enrichment of beneficial bacteria in the intestine, and dietary interventions have been shown to manage inflammatory bowel diseases, potentially serving as a radiomitigation strategy.

ACE inhibitors effectively decreased the incidence of radiation pneumonitis in most patients with lung cancer. In particular, captopril demonstrated significant, safe, and effective protective effects against both renal and pulmonary injury. Moreover, prophylactic administration of captopril mitigated radiation-induced hypertension and renal failure, as well as reduced lung endothelial dysfunction, radiation pneumonitis, and fibrosis [23].

In male C57BL/6J mice, Simvastatin reduced radiation-induced intestinal damage to a limited extent, which was confirmed by improved mucosal structural integrity, reduced neutrophil infiltration, decreased thickening of the intestinal wall, and decreased accumulation of collagen I in the jejunum and bone marrow. Simvastatin also inhibited irradiation-induced marrow adipogenesis and radio-protected bone marrow niche cells [24]. The radiomitigators described above are presented in tab. 2.

CURRENT ISSUES AND LIMITATIONS

Development and clinical application of effective radioprotectors face some fundamental challenges that limit their widespread use.

Synthetic radioprotectors exhibit an inverse relationship between effectiveness and toxicity, which is the most serious limitation. Most radioprotectors have a narrow therapeutic window as the dose required to protect healthy tissues from radiation is very close to the dose that causes serious side effects. Amifostine, which is the gold standard, causes dose-dependent hypotension, nausea, vomiting, and nephrotoxicity, requires close patient monitoring and is approved for limited clinical indications. In addition, to achieve maximum radioprotection, doses approaching the maximum tolerated dose are required. It makes the risk of adverse drug reactions unacceptably high, especially when used for prophylactic purposes.

Lack of selectivity is the next limitation. The majority of radioprotectors (synthetic and natural) are designed to protect all body cells, including malignant ones. Protecting healthy tissues during radiation therapy can create a paradox where minimizing damage to surrounding healthy cells may inadvertently protect neighboring tumor cells, potentially reducing patient survival.

The main area of research is development of strategies for selective protection of normal tissues. The most promising strategy is targeted delivery of protectors using nanocarriers functionalized with ligands that target receptors primarily expressed on healthy tissues.

CONCLUSION

The analysis of modern scientific data shows that the problem of protection from ionizing radiation remains an extremely urgent challenge for radiobiology and medicine. Despite many years of research, the ideal and easy-to-use radioprotector with high efficacy and a favorable safety profile has not yet been found..