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

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-[2ʹ-(3,4-dimethoxyphenyl)-59benzimidazolyl] 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 freeradical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD 50 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 5 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.

Pharmacokinetics of Cajaninstilbene Acid and Its Main Glucuronide Metabolite in Rats

“…V ss (0.84 L/kg) of CSA was substantially greater than the total blood volume (approximately 0.0312 L/kg) of rats, and t 1/2, λz was relatively long, indicating that CSA had an extensive affinity with the tissues rather than plasma protein and was readily distributed into the extravascular system . This is in agreement with the study of Hua et al, where CSA underwent a rapid and wide distribution in tissues and organs throughout the whole body, especially in the small intestine, liver, and kidneys.…”

“…readily distributed into the extravascular system. 26 This is in agreement with the study of Hua et al, 19 where CSA underwent a rapid and wide distribution in tissues and organs throughout the whole body, especially in the small intestine, liver, and kidneys. After oral administration, CSA was absorbed rapidly into the circulation to reach C max (2.77 μM) at approximately 21 min and eliminated slowly with a t 1/2,λz of 12.90 h, CL/F of 3.54 L h −1 kg −1 , and relatively large V d /F of 54.64 L/kg.…”

Appraisal of biochemical classes of radioprotectors: evidence, current status and guidelines for future development

“…H33342 derivatives such as tris (TBZ), and dimethoxty (DMA) benzimidazole were also studied for their radioprotective efficacy in vivo. DMA showed an effective radioprotection in mice at single nontoxic oral dose with a DMF of 1.28 (Nimesh et al 2015). DMA-treated mice showed delayed radiation sickness, such as weight loss, irritability and lethargy.…”

Radioprotective Agents: Strategies and Translational Advances

“…Further mechanistic study revealed that DMA exhibits radioprotective activity by activating NFκB signaling through NIK/IKK pathway in vitro as well as in vivo . DMA when administered 2 hr prior to 8 Gy whole‐body irradiation showed an impressive rescue of radiation‐induced morbidity, in terms of weight loss and mortality, without a change in tumor response …”