The Ability of the Nitric Oxide Synthases Inhibitor T1023 to Selectively Protect the Non-Malignant Tissues.

Marina Filimonova,Sergey Ivanov,Nina Yakovleva,Petr Shegay,Andrey Kaprin,Valentina Surinova,Vyacheslav Saburov,Sergey Koryakin,Victoria Makarchuk,Alexander Filimonov,Larisa Sevankaeva,Ljudmila Shevchenko,Alina Saburova,Vadim Yuzhakov

doi:10.3390/ijms22179340

Abstract

Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)—1.6–1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5–1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4–1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors—T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.

Highlights

Introduction published maps and institutional affilThe frequency of cancer incidence is steadily increasing in almost all countries of the world
We showed that some S-alkyl-N-acyl-substituted isothioureas are effective competitive inhibitors of nitric oxide synthases (NOS) capable of causing a pronounced vasoconstrictor, vasopressor effect [13,14]
By 10–13 days after LI in control rats, the severity of acute RSR corresponded to grades 2–3 according to the RTOG scale

Summary

Introduction

Introduction published maps and institutional affilThe frequency of cancer incidence is steadily increasing in almost all countries of the world. Dose fractionation and conformal radiation techniques along with molecular targeted therapy have improved the preservation of normal cells/tissues during radiation treatment [2]. Despite such efforts, patients in 10–15% of cases (and in some local tumors, up to 40%) are faced with the complications arising from radiation damage to normal tissues [3,4,5]. Patients in 10–15% of cases (and in some local tumors, up to 40%) are faced with the complications arising from radiation damage to normal tissues [3,4,5] Such complications are able to limit the possibility of cancer therapy in full. Some pathologies, especially late radiation injuries, which are based on the processes of fibrogenesis, are iations

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