Investigation of toxicological properties and optimal therapeutic doses of compound T1084 with anti-tumor activity

Antiangiogenic therapy, despite its effectiveness, is limited by systemic toxicity, the development of organism resistance, and high treatment costs. In this regard, the development of new, safer, and more effective antiangiogenic agents is a relevant task in modern oncology.

The aim. Assessment of toxicological characteristics and experimental substantiation of the optimal range of therapeutic doses of an NOS/PDK inhibitor (compound T1084) for enteral administration.

Materials and methods. The study was conducted on 118 BALB/c mice and 79 F1 hybrids (CBA×C57BL/6j). The acute toxicity of compound T1084 was studied following a single enteral administration. Cumulative effects were assessed using the Lim method with parenteral administration. The optimal range of anti-tumor doses was investigated on a model of Ehrlich’s solid carcinoma therapy with subchronic enteral administration of compound T1084 at doses of 200–400 mg/kg.

Results. Parameters of acute toxicity for compound T1084 upon enteral (intragastric) administration were established: LD₁₀ — 2031 mg/kg, LD₁₆ — 2100 mg/kg, LD₅₀ — 2356±15 mg/kg, LD₈₄ — 2644 mg/kg. According to toxicological studies, compound T1084, when administered enterally, belongs to hazard class III (moderately hazardous substances) according to GOST 12.1.007–76 and class V according to GOST 32419–2022 for the EAEU. A 5-fold decrease in the toxicity of T1084 was revealed with enteral administration compared to parenteral administration. The absence of cumulative properties in T1084 was established, which allows for prolonged courses of this compound. On the Ehrlich’s carcinoma therapy model, a dose-dependent anti-tumor effect was shown: at 200 mg/kg, tumor growth inhibition (TGI) was 15–20%; 300 mg/kg — 28–31%; 400 mg/kg — 30–35%. The absence of significant differences between doses (300 and 400 mg/kg) with more favorable tolerability allowed the selection of 300 mg/kg as the optimal dose.

Conclusion. The obtained data substantiate the promise of preclinical development of an oral dosage form of T1084 for long-term therapy in oncology, including in adjuvant treatment regimens.

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