Evaluation of the antitumor effect of 2-(1,1-Dimethyl-1h-benzo[E]indol-2-Yl)-5,6,7-trichloro-1,3-tropolone in in vivo models in monotherapy mode.

Abstract

e14058 Background: This study evaluated the in vivo efficacy and safety of JO-122(2) (2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone), a newly synthesized compound, in a subcutaneous U87MG glioblastoma xenograft model. Methods: The novel compound JO-122(2) was administered intragastrically as a starch gel/DMSO suspension (0.2 mL, 3x/week for 25 days) to BALB/c nude mice bearing U87MG glioblastoma xenografts. The study was conducted in two stages. In the first stage, 24 animals (four males and four females per group) were divided into four groups: JO-122(2) at doses of 10, 20, or 30 mg/kg (administered intragastrically three times per week) and a control group (1% starch gel with DMSO). Since there was no significant effect, the second stage investigated doses of 40, 50, and 60 mg/kg (groups 5–7), as well as a control group (group 8), for a total of 32 animals. Tumor growth dynamics were assessed every three days, starting from the first administration of the compounds. The analysis included tumor growth inhibition (TGI), body weight, and organ-to-body weight ratios (liver, kidneys, spleen, heart, and lungs). Hematological and biochemical blood parameters were also analyzed. Statistical analysis accounted for sex; when no differences were observed, the data were pooled. Results: At doses of 10–30 mg/kg, no differences in tumor growth were detected compared to the control group. On day 25, the tumor volumes were 1,437.86 ± 121.03 mm³ (10 mg/kg), 1,256.02 ± 201.64 mm³ (20 mg/kg), and 1,291.35 ± 252.15 mm³ (30 mg/kg), versus 1,430.87 ± 284.21 mm³ in the control group. In the second stage, at doses of 40–60 mg/kg, pronounced dose-dependent antitumor activity was observed. On day 25, the tumor volume in the 60 mg/kg group was 784.47 ± 142.62 mm³ (1.65 times smaller than the control group's volume of 1,297.41 ± 153.53 mm³; p < 0.0083), with TGI reaching 39.54%. The relative tumor weight decreased to 6.02% ± 1.23% (control: 12.94% ± 2.71%; p < 0.0083). At a dose of 50 mg/kg, the tumor volume was 853.68 ± 107.46 mm³ (TGI: 34.20%), and at 40 mg/kg, the tumor volume was 1,098.5 ± 229.43 mm³. Toxicity was assessed based on body weight stability (initial/final: 20.50–27.50 g/21.50–31.50 g), organ-to-body weight ratios, and laboratory parameters. Hematological analysis revealed no differences in 12 parameters. Biochemical indicators also did not exceed control values. Conclusions: JO-122(2) demonstrates significant in vivo antitumor activity only at doses ≥50 mg/kg, inhibiting glioblastoma growth by 34.2–39.5% (TGI). The low efficacy at doses of 10–30 mg/kg is likely due to the limited bioavailability of the compound. The obtained data justify the potential of JO-122(2) for further studies, including investigation of its mechanisms of action (presumably, inhibition of proliferative signaling pathways) and optimization of the dosing regimen.