Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

Mol Pharmacol. 2015 Oct;88(4):768-78. doi: 10.1124/mol.115.098376. Epub 2015 Aug 3.

Abstract

Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its free-radical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD50 of >2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C(max) = 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that (99m)Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacokinetics*
  • Benzimidazoles / toxicity*
  • Bisbenzimidazole / metabolism
  • Bisbenzimidazole / pharmacokinetics
  • Bisbenzimidazole / toxicity
  • Carcinoma, Ehrlich Tumor / drug therapy
  • Carcinoma, Ehrlich Tumor / metabolism
  • Carcinoma, Ehrlich Tumor / radiotherapy
  • Dose-Response Relationship, Radiation
  • Drug Evaluation, Preclinical / methods
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics*
  • Piperazines / toxicity*
  • Radiation-Protective Agents / metabolism
  • Radiation-Protective Agents / pharmacokinetics*
  • Radiation-Protective Agents / toxicity*
  • Survival Rate / trends
  • Tissue Distribution / drug effects
  • Tissue Distribution / physiology

Substances

  • 5-(4-methylpiperazin-1-yl)-2-(2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyl)benzimidazole
  • Benzimidazoles
  • Piperazines
  • Radiation-Protective Agents
  • Bisbenzimidazole