- Please check and comment entries here.
Nitric Oxide Synthases Inhibitor T1023
A nitric oxide synthase (NOS) inhibitor, compound T1023 induce transient hypoxia and prevent acute radiation syndrome (ARS) in mice. Significant efficacy and safety in radioprotective doses (1/5–1/4 LD10) can prove its ability to prevent complications of tumor radiation therapy (RT).
The frequency of cancer incidence is steadily increasing in almost all countries of the world. Over 3 million patients are currently registered with cancer in the Russian Federa-tion . About 50–70% of them receive different types of radiation therapy (RT) that re-mains one of the most effective tools in cancer therapy. The ongoing efforts towards de-signing new radiation treatment techniques are aimed to improve the quality of life of cancer patients and to minimize the toxicity of radiotherapy. Dose fractionation and con-formal radiation techniques along with molecular targeted therapy have improved the preservation of normal cells/tissues during radiation treatment. But despite such efforts patients in 10–15% of cases (and in some locales tumors—up to 40%) are faced with the complications arising from radiation damage to normal tissues . Such complications are able to limit the possibility of cancer therapy in full. Moreover, some pathologies, espe-cially late radiation injuries, which are based on the processes of fibrogenesis, are difficult to cure with conservative therapy. In some cases, they can become threatening, capa-ble of lead to failure of internal organs and death. It is obvious that minimizing such RT risks requires versatile efforts aimed at both further improving medical radiological techniques, methods of planning radiation exposure, and, on the other hand, developing new approaches to pharmacological prevention and treatment of radiation injuries.
The NOS inhibitor 1-isobutanoyl-2-isopropylisothiourea hydrobromide (compound T1023) is high-ly effective (dose modifying factor (DMF)—1.6–1.9) in the prevention of H-ARS and G-ARS in mice . The data on the T1023 significant radioprotective activity and the relative safety of its effective dose (1/5–1/4 LD10) become the reason for studying its ability to pro-tect normal somatic tissues in models of acute radiation damage to the skin, as well as its radiation modifying effects in RT models.
The problem of developing pharmacological agents for the prevention and treatment of RT toxic effects have currently attracted considerable attention. The objects of research and development in this area are an extremely wide range of synthetic and biotechnolog-ical compounds with various types of biochemical and pathophysiological activity: the ability to limit the formation of primary radiation damage, modulate the processes of cell death, the activity of post-radiation repair, the course of immune-inflammatory processes and fibrogenesis .
The ability of ‘direct’ radioprotectors (that are effective during the physical and phys-icochemical stages of injury) to limit the development of radiation toxic effects seems to be quite natural, since primary molecular damage is the pathophysiological basis of such pathologies. This is confirmed by the presence of such abilities in aminothiol radioprotec-tors , adrenergic and serotonergic hypoxic radioprotectors, antioxidants and inhibitors of radiolysis products [32,33]. NOS inhibitors may complement the list of such agents.
The prophylactic effect of T1023 against ARS (DMF—1.6–1.9) develops according to physiological mechanisms that are characteristic, among others, for the agonists of α1B-adrenoreceptors and serotonin 5-HT2-receptors. Rapid and pronounced vas-oconstriction causes reflex changes in cardiac activity (decrease in strength and frequency of contractions) that limit systemic blood flow (for T1023: cardiac output is reduced by 40–50% within 90–120 min). The resulting transient hypoxia promotes to limit alteration un-der radiation exposure.
Considering such a mechanism of radioprotective activity, it is quite natural that T1023 is also capable of reducing the toxic effects of γ-radiation in normal tissues. The prophylactic use of T1023 in the optimal radioprotective dose (75 mg/kg; 1/4 LD10) leads to effective (DMF—1.4–1.7) and pronounced limitation of the development of radiation damage to the skin and underlying tissues in mice and rats. The histological data confirmed that these effects of T1023 developed due to a decrease in radiation alteration of normal tissues and the preservation of the functional activity of cell populations that are critical in the development of radiation burn.
Means of prevention of RT complications, acceptable for clinical use, must be protec-tive for normal tissues, it must not defense tumor cells and weaken the antitumor efficacy of radiation exposure. For example, the clinical radioprotector amifostine has such ability. The selectivity of its effects is associated with the accumulation of its active metabolite WR-1065, mainly in normal tissues, due to hypovascularization of solid tumors and low expression of alkaline phosphatase in tumor cells.
Researches on RT models of different solid tumors (ectodermal ESC in mice and mesodermal M1S in rats) showed that T1023 also fully implements the selective radioprotective effect. T1023 significantly limited the severity of RSR in normal animal tissues with all variants of RT (single or hypofractionated γ-ray LI). However, mani-festations of the radioprotective effect of T1023 in the malignant tissues of M1S and ESC have not been proved. T1023 and amifostine can offer equally effective selective protection for normal tissues. It is important to empha-size that T1023 was used in rather less toxic dose than amifostine.
There is no experimental data that directly reflect the mechanism of the selec-tivity of T1023 radioprotective effect. However, as with amifostine, the selectivity of T1023 appears to be due to the pathophysi-ology of solid tumors. It is known that atypical angioarchitecture and functional insuffi-ciency of the vascular network of such neoplasias determine the presence of chronic in-tratumoral hypoxia in their tissues. According to clinical studies in solid human tumors, about 34% of cells are in deep chronic hypoxia (pO2 < 5 mm Hg), regardless of histogenesis and stage of the process, which halves their radiosensitivity. In contrast, in normal tissues such fraction does not exceed 0.5% [36,37]. Under these conditions, T1023-induced transient hypoxia significantly alters the level of oxygenation and radio-sensitivity of normal tissues. This provides prevention of ARS for γ-ray total body irradia-tion and toxic effects for γ-ray LI. However, in tissues of solid tumors, the scale of modifi-cation of oxygenation and radiosensitivity can be significantly limited by the initial intra-tumoral hypoxia and the initial radioresistance of neoplasia. In addition, the T1023 selec-tivity can also be facilitated by functional insufficiency of tumor vasculature, which, among other things, manifests in a weak, unstable and, often, paradoxical reaction of ves-sels and tumor blood flow to the action of vasopressors and vasodilators.
The entry is from 10.3390/ijms22179340
- Zaridze, D.G.; Kaprin, A.D.; Stilidi, I.S. Dynamics of morbidity and mortality from malignant tumors in Russia. Vopr. Onkol. 2018, 64, 578–591. (In Russian) [Google Scholar]
- Baskar, R.; Lee, K.A.; Yeo, R.; Yeoh, K.W. Cancer and Radiation therapy: Current advances and future directions. Int. J. Med. Sci. 2012, 9, 193–199. [Google Scholar] [CrossRef] [PubMed]
- Lushnikov, E.F.; Abrosimov, A.Y. Modern Radiation Pathology of Human: Problems of Methodology, Etiology, Pathogenesis and Classification; Medical Radiological Research Center of the Ministry of Health of the Russian Federation: Obninsk, Russia, 2012; 235p. (In Russian) [Google Scholar]
- Joye, I.; Haustermans, K. Early and late toxicity of radiotherapy of rectal cancer. Recent Results Cancer Res. 2014, 203, 189–201. [Google Scholar] [PubMed]
- Meattini, I.; Guenzi, M.; Fozza, A.; Vidali, C.; Rovea, P.; Meacci, F.; Livi, L. Overview on cardiac, pulmonary and cutaneous toxicity in patients treated with adjuvant radiotherapy for breast cancer. Breast Cancer 2017, 24, 52–62. [Google Scholar] [CrossRef]
- Stubblefield, M.D. Clinical evaluation and management of radiation fibrosis syndrome. Phys. Med. Rehabil. Clin. N. Am. 2017, 28, 89–100. [Google Scholar] [CrossRef]
- Strojan, P.; Hutcheson, K.A.; Eisbruch, A.; Beitler, J.J.; Langendijk, J.A.; Lee, A.W.M.; Corry, J.; Mendenhall, W.M.; Smee, R.; Rinaldo, A.; et al. Treatment of late sequelae after radiotherapy for head and neck cancer. Cancer Treat. Rev. 2017, 59, 79–92. [Google Scholar] [CrossRef]
- Fliedner, T.M.; Dorr, D.H.; Meineke, V. Multi-organ involvement as a pathogenetic principle of the radiation syndromes: A study involving 110 case histories documented in SEARCH and classified as the bases of haematopoietic indicators of effect. BJR 2005, 78 (Suppl. 27), 1–8. [Google Scholar] [CrossRef]
- Satyamitra, M.M.; DiCarlo, A.L.; Taliaferro, L. Understanding the pathophysiology and challenges of development of medical countermeasures for radiation -induced vascular/endothelial cell injuries: Report of a NIAID workshop, August 20, 2015. Radiat. Res. 2016, 186, 99–111. [Google Scholar] [CrossRef]
- Moding, E.J.; Kastan, M.B.; Kirsch, D.G. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat. Rev. Drug Discov. 2013, 12, 526–542. [Google Scholar] [CrossRef]
- Kim, J.H.; Jenrow, K.A.; Brown, S.L. Mechanisms of radiation -induced normal tissue toxicity and implications for future clinical trials. Radiat. Oncol. J. 2014, 32, 103–115. [Google Scholar] [CrossRef]
- Montay-Gruel, P.; Meziani, L.; Yakkada, C.; Vozenin, M. Expanding the therapeutic index of radiation therapy by normal tissue protection. Br. J. Radiol. 2019, 92, 20180008. [Google Scholar] [CrossRef]
- DiCarlo, A.L.; Bandremer, A.C.; Hollingsworth, B.A.; Kasim, S.; Laniyonu, A.; Todd, N.F.; Wang, S.-J.; Wertheimer, E.R.; Rios, C. Cutaneous radiation injuries: Models, assessment and treatments. Radiat. Res. 2020, 194, 315–344. [Google Scholar] [CrossRef] [PubMed]
- Singh, V.K.; Garcia, M.; Seed, T.M. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int. J. Radiat. Biol. 2017, 93, 870–884. [Google Scholar]
- Singh, V.K.; Hanlon, B.K.; Santiago, P.T.; Seed, T.M. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: Part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use. Int. J. Radiat. Biol. 2017, 93, 885–906. [Google Scholar] [PubMed]
- Grebenyuk, A.N.; Gladkikh, V.D. Modern condition and prospects for the development of medicines towards prevention and early treatment of radiation damage. Biol. Bull. 2019, 46, 1540–1555. [Google Scholar] [CrossRef]
- Kouvaris, J.R.; Kouloulias, V.E.; Vlahos, L.J. Amifostine: The first selective-target and broad-spectrum radioprotector. Oncologist 2007, 12, 738–747. [Google Scholar] [CrossRef] [PubMed]
- King, M.; Joseph, S.; Albert, A.; Thomas, T.V.; Nittala, M.R.; Woods, W.C.; Vijayakumar, S.; Packianathan, S. Use of amifostine for cytoprotection during radiation therapy: A review. Oncology 2020, 98, 61–80. [Google Scholar] [CrossRef] [PubMed]
- Khussar, I.P. Protective action of cystamine on thyroid tissue in acute radiation injury. Tsitologiia 1963, 5, 91–93. (In Russian) [Google Scholar]
- Vasin, M.V.; Ushakov, I.B.; Suvorov, N.N. Radioprotective effectiveness of indralin in local gamma irradiation of skin. Radiat. Biol. Radioecol. 1998, 38, 42–54. (In Russian) [Google Scholar]
- Vasin, M.V.; Ushakov, I.B.; Korovkina, E.P.; Kovtun, V.Y. Radioprotective capacity of indralin in reducing radiation injury to salivary glands. Radiat. Biol. Radioecol. 2004, 44, 333–335. (In Russian) [Google Scholar]
- Turgunov, M.B.; Sorokina, I.D.; Turusov, V.S. Effect of 5-methoxytryptamine on cutaneous changes caused by ionizing radiation in mice and rats. Med. Radiol. 1964, 9, 70–74. (In Russian) [Google Scholar]
- Cho, Y.J.; Yi, C.O.; Jeon, B.T.; Jeong, Y.Y.; Kang, G.M.; Lee, J.E.; Roh, G.S.; Lee, J.D. Curcumin attenuates radiation-induced inflammation and fibrosis in rat lungs. Korean J. Physiol. Pharmacol. 2013, 17, 267–274. [Google Scholar] [CrossRef] [PubMed]
- Guven, B.; Can, M.; Piskin, O.; Aydin, B.G.; Karakaya, K.; Elmas, O.; Acikgoz, B. Flavonoids protect colon against radiation induced colitis. Regul. Toxicol. Pharmacol. 2019, 104, 128–132. [Google Scholar] [CrossRef] [PubMed]
- Anderson, C.M.; Sonis, S.T.; Lee, C.M.; Adkins, D.; Allen, B.G.; Sun, W.; Agarwala, S.S.; Venigalla, M.L.; Chen, Y.; Zhen, W.; et al. Phase 1b/2a trial of the superoxide dismutase mimetic GC4419 to reduce chemoradiotherapy-induced oral mucositis in patients with oral cavity or oropharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2018, 100, 427–435. [Google Scholar] [CrossRef]
- Shrishrimal, S.; Kosmacek, E.A.; Chaterjee, A.; Tyson, M.J.; Oberly-Deegan, R.E. The SOD mimic, MnTE-2-PyP, protects from chronic fibrosis and inflammation in irradiated pelvic tissues. Antioxidants 2017, 6, 87. [Google Scholar] [CrossRef] [PubMed]
- Dvorak, H.F. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am. J. Pathol. 2003, 162, 1747–1757. [Google Scholar] [CrossRef]
- Goel, S.; Duda, D.G.; Xu, L.; Munn, L.L.; Boucher, Y.; Fukumura, D.; Jain, R.K. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 2011, 93, 1071–1121. [Google Scholar] [CrossRef] [PubMed]