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

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

Author information

1
Chemical Biology Research Laboratory, Special Center for Molecular Medicine, Jawaharlal Nehru University, Delhi, India (V.Ta.); Department of Chemistry, University of Delhi, Delhi, India (H.N., V.Ti., V.Ta.); Department of Biology, Georgia State University, Atlanta, Georgia (C.Y., S.R.G., R.A.); Dr. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India (A.K.); Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India (K.C., P.P.H., A.K.M.); and Pharmacokinetics and Metabolism Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India (A.S., J.L.).
2
Chemical Biology Research Laboratory, Special Center for Molecular Medicine, Jawaharlal Nehru University, Delhi, India (V.Ta.); Department of Chemistry, University of Delhi, Delhi, India (H.N., V.Ti., V.Ta.); Department of Biology, Georgia State University, Atlanta, Georgia (C.Y., S.R.G., R.A.); Dr. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India (A.K.); Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India (K.C., P.P.H., A.K.M.); and Pharmacokinetics and Metabolism Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India (A.S., J.L.) vtandon@mail.jnu.ac.in.

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.

PMID:
26240287
DOI:
10.1124/mol.115.098376
[Indexed for MEDLINE]

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