RT Journal Article
SR Electronic
T1 Preclinical Evaluation of DMA, a Bisbenzimidazole as Radioprotector: Toxicity, Pharmacokinetics and Biodistribution Studies in Balb/c Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.098376
DO 10.1124/mol.115.098376
A1 Hemlata Nimesh
A1 Vinod Tiwari
A1 Chunhua Yang
A1 Sushma R Gundala
A1 Krishna Chuttani
A1 Puja P Hazari
A1 Anil K Mishra
A1 Abhisheak Sharma
A1 Jawahar Lal
A1 Anju Katyal
A1 Ritu Aneja
A1 Vibha Tandon
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/08/03/mol.115.098376.abstract
AB Radiotherapy, a therapeutic modality of cancer treatment, non-selectively damages normal tissues over tumor tissue as well. A continuous search is going on for the development of therapeutic agents, which selectively reduce radiation induced normal tissue injury without reducing tumoricidal effect, thereby increasing therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimi-dazole (DMA) as non-cytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose reduction factor (DRF) of 1.28. ORAC assay confirmed its free radical quenching ability. Single bolus dose and 28-days repeated administration of DMA in mice for toxicity studies determined LD50 of >2000 mg/kg bw and 225 mg/kg bw respectively, suggesting DMA is safe. Histopathology, biochemical parameters and relative organ weight analysis revealed insignificant changes in DMA treated animals. Pharmacokinetic study of DMA at oral and intravenous doses showed its Cmax = 1h, bioavailability of 8.84%, elimination half-life of 4h and an enterohepatic recirculation. Biodistribution study in Ehrlich Ascites Tumor (EAT) bearing mice showed that 99mTc-DMA achieved highest concentration in 1h and retained upto 4h in lungs, liver, kidneys and spleen, and in a low concentration in tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that single dose treatment of tumor bearing mice with DMA 2h prior to 8 Gy TBI, showed an impressive rescue of radiation induced morbidity, in terms of weight loss and mortality, without a change in tumor response.