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Research ArticleArticle

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

Hemlata Nimesh, Vinod Tiwari, Chunhua Yang, Sushma R. Gundala, Krishna Chuttani, Puja P. Hazari, Anil K. Mishra, Abhisheak Sharma, Jawahar Lal, Anju Katyal, Ritu Aneja and Vibha Tandon
Molecular Pharmacology October 2015, 88 (4) 768-778; DOI: https://doi.org/10.1124/mol.115.098376
Hemlata Nimesh
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.)
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Vinod Tiwari
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.)
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Chunhua Yang
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.)
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Sushma R. Gundala
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.)
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Krishna Chuttani
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.)
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Puja P. Hazari
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.)
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Anil K. Mishra
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.)
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Abhisheak Sharma
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.)
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Jawahar Lal
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.)
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Anju Katyal
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.)
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Ritu Aneja
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.)
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Vibha Tandon
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.)
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This article has a correction. Please see:

  • Correction to: “Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice” - October 01, 2015

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)-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 Cmax = 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 99mTc-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.

Footnotes

    • Received February 12, 2015.
    • Accepted July 29, 2015.
  • Council of Scientific and Industrial Research, Department of Biotechnology and Department of Science and Technology, and the government of India for funding.

  • dx.doi.org/10.1124/mol.115.098376.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (4)
Molecular Pharmacology
Vol. 88, Issue 4
1 Oct 2015
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Research ArticleArticle

Bisbenzimidazole Pharmacologic Study, DMA as Radioprotector

Hemlata Nimesh, Vinod Tiwari, Chunhua Yang, Sushma R. Gundala, Krishna Chuttani, Puja P. Hazari, Anil K. Mishra, Abhisheak Sharma, Jawahar Lal, Anju Katyal, Ritu Aneja and Vibha Tandon
Molecular Pharmacology October 1, 2015, 88 (4) 768-778; DOI: https://doi.org/10.1124/mol.115.098376

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Research ArticleArticle

Bisbenzimidazole Pharmacologic Study, DMA as Radioprotector

Hemlata Nimesh, Vinod Tiwari, Chunhua Yang, Sushma R. Gundala, Krishna Chuttani, Puja P. Hazari, Anil K. Mishra, Abhisheak Sharma, Jawahar Lal, Anju Katyal, Ritu Aneja and Vibha Tandon
Molecular Pharmacology October 1, 2015, 88 (4) 768-778; DOI: https://doi.org/10.1124/mol.115.098376
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