Antitumor efficacy of combined NOS/PDK inhibitor T1084 and gamma radiation in an experimental model

One of the approaches to overcoming the problem of tumor radioresistance, which significantly limits the effectiveness of radiotherapy, is the combination of different treatment strategies, including the use of anti-angiogenic agents. However, the drawbacks of existing anti-angiogenic drugs (toxicity, high cost) indicate the need to develop new, safer, and more effective agents of this class.

Purpose of the study. To investigate the efficacy of an experimental combined antitumor therapy that integrates radiation exposure with subchronic parenteral administration of compound T1084, which exhibits anti-angiogenic and hypoxia-targeted cytotoxic activity.

Materials and methods. The study examined the bifunctional compound T1084 (1‑isobutanoyl‑2‑isopropylisothiourea dichloroacetate), which has dual inhibitory activity against nitric oxide synthases (NOS) and pyruvate dehydrogenase kinase (PDK). The compound was developed and synthesized at the A. Tsyb Medical Radiological Research Center (Patent RU2699558). Antitumor efficacy was evaluated in a transplanted solid Ehrlich carcinoma (SEC) model in 149 F1(CBA×C57Bl/6j) mice across two independent experiments performed according to a unified protocol. The animals were divided into four groups: control (tumor-bearing animals), local irradiation of the tumor (10 Gy single dose or 20 Gy fractionated), monotherapy with T1084 (70.7 mg/kg, daily intraperitoneal administration), and combined therapy (T1084 plus gamma irradiation). Irradiation was performed using the Rokus-M gamma unit (⁶⁰Co, 1 Gy/min), and dosimetry was carried out according to the standards of the International Atomic Energy Agency (IAEA). Tumor development was assessed morphometrically.

Results. It was demonstrated that subchronic application of T1084 at a safe dose of 70.7 mg/kg (1/4 LD₁₆) significantly enhanced the antitumor efficacy of different radiotherapy regimens without impairing treatment tolerability or inducing toxic effects. In two independent SEC experiments, the combination therapy produced a consistent and statistically significant antitumor effect (TI = 45–50 %), exceeding the efficacy of radiotherapy alone and of T1084 monotherapy. Conclusion. The experimental data obtained support the rationale for using the NOS/PDK inhibitor T1084 in combination with radiotherapy for the treatment of radioresistant solid tumors characterized by high angiogenic activity.

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