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The Ability of the Nitric Oxide Synthases Inhibitor T1023 to Selectively Protect the Non-Malignant Tissues
Marina Filimonova1, Alina Saburova1, Victoria Makarchuk1
1A. Tsyb Medical Radiological Research Center-Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia.
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.
Insights
Nitric oxide synthase inhibitor T1023 selectively protects normal tissues from radiation damage. This compound limits radiation-induced skin reactions and acute radiation syndrome, offering a promising strategy for preventing radiotherapy complications.
Area of Science:
- Oncology
- Radiation Biology
- Pharmacology
Background:
- Nitric oxide synthase (NOS) inhibitors, like compound T1023, have previously demonstrated radioprotective effects against acute radiation syndrome (ARS) in mice.
- The efficacy and safety profile of T1023 in preventing ARS prompted further investigation into its potential for mitigating radiation therapy (RT)-induced complications.
Purpose of the Study:
- To evaluate the efficacy of T1023 in preventing acute radiation-induced skin reactions (RSR) in both non-tumor-bearing and tumor-bearing animals.
- To determine if T1023's radioprotective effects are selective for normal tissues without compromising the antitumor efficacy of radiation therapy.
Main Methods:
- T1023 was administered to rats and mice before irradiation.
- Acute radiation skin reactions were assessed using clinical, morphological, histological, and RTOG classification methods.
- The study included models with and without solid tumors to evaluate selectivity.
Main Results:
- Pre-irradiation administration of T1023 significantly reduced the severity of acute radiation skin reactions.
- T1023 demonstrated a dose modifying factor (DMF) of 1.4-1.7 for skin protection.
- In tumor models, T1023 selectively protected normal tissues, reducing skin reactions without affecting the antitumor response of gamma radiation.
Conclusions:
- Compound T1023 selectively protects normal tissues from gamma radiation-induced damage through a hypoxic mechanism.
- T1023 effectively limits acute radiation skin reactions and holds potential for preventing radiotherapy complications.
- NOS inhibitors represent a promising therapeutic avenue for enhancing the safety and efficacy of radiation therapy.
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