The problem of developing radioprotective means, capable of mitigating the effects of radiation exposure on the body, is associated not only with the danger of terrorist, military incidents or emergencies at nuclear facilities. An important area for the use of radioprotectors is space exploration, in particular, the need for crew members, protected only by a spacesuit, to enter open space. Furthermore, the solution to the problem of radiotherapy complications in oncology can also be the use of selective radioprotectors able to protect healthy tissues without reducing the effectiveness of tumor radiotherapy. An example of such approach is the use of amifostine in radiotherapy of a number of head-neck tumors.
It is important to understand that the developed means should be well tolerated not only by healthy volunteers, but also by people of different ages, physical conditions, including the elderly and debilitated cancer patients. In particular, the adverse effects of amifostine in its effective radioprotective doses lead to a significant limitation of its clinical use.
The solution to the problem of radioprotector safety can be the development of combinations containing several radiomodifying substances in small doses. Such compositions are capable of providing a synergistic radioprotective effect and good patient tolerance.
Compounds capable of selectively inhibiting endothelial and inducible nitric oxide synthase (NOS) could be the base of such combinations. We have shown that NOS-inhibitors, in particular, N,S-substituted isothioureas, are highly effective in relatively safe doses. For example, the optimal radioprotective dose of one of them, T1023, with dose modifying factor (DMF) of 1.6 - 1.8, is 1/5-1/4 LD10.
It has been shown that T1023 and its derivatives are highly effective both for parenteral and oral administration. These compounds provide pronounced prophylaxis of bone marrow and intestinal forms of acute radiation syndrome. Moreover, they are capable to effectively, with a DMF of 1.45, provide the prophylaxis of early and late complications in mouse and rat models of single and fractionated radiotherapy of solid tumors. It is important that the use of these compounds does not reduce the effectiveness of radiotherapy.
The radioprotective effect of these compounds is realized by a specific molecular mechanism - by suppressing the endothelium-dependent eNOS/sGC/cGMP pathway of vascular relaxation. The mechanism of radioprotective activity of NOS inhibitors brings them with vasoactive radioprotectors - α1-adrenoreceptor agonists and 5-HT2 serotonin receptors. Therefore, their combined use is accompanied by a synergistic radioprotective effect. This opens up prospects for the creation of highly effective and safe radioprotector combinations.
Keywords: radiation pathologies; selective radioprotector; safety; NOS inhibitor; combined use