title: 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-[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.
authors.affiliation: 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.).
authors.forename: Hemlata
authors.initials: H
authors.lastname: Nimesh
authors.affiliation: 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.).
authors.forename: Vinod
authors.initials: V
authors.lastname: Tiwari
authors.affiliation: 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.).
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yang
authors.affiliation: 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.).
authors.forename: Sushma R
authors.initials: SR
authors.lastname: Gundala
authors.affiliation: 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.).
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.affiliation: 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.).
authors.forename: Puja P
authors.initials: PP
authors.lastname: Hazari
authors.affiliation: 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.).
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
authors.affiliation: 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.).
authors.forename: Abhisheak
authors.initials: A
authors.lastname: Sharma
authors.affiliation: 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.).
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.affiliation: 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.).
authors.forename: Anju
authors.initials: A
authors.lastname: Katyal
authors.affiliation: 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.).
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
authors.affiliation: 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.
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D006690:Bisbenzimidazole / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D011837:Radiation-Protective Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D015996:Survival Rate / Q000639:trends; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: C477187:5-(4-methylpiperazin-1-yl)-2-(2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyl)benzimidazole; D001562:Benzimidazoles; D010879:Piperazines; D011837:Radiation-Protective Agents; D006690:Bisbenzimidazole