Evaluation of dimethoxydop-NU as a novel anti-tumor agent.
Dimethoxydop-NU, 1-[2-{3-(2-Chloroethyl)-3-nitrosoureido}ethyl]-3,4-dimethoxy-benzene (Compound 1), was synthesized from 3,4-dimethoxy-phenethylamine as a novel anti-tumor agent based on the structures of the clinical drug CCNU and dopamine, an important endogenous biological amine having anti-angiogenesis property. In vitro screening in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937, revealed its cytotoxicity greater than that of hydroxyurea and comparable to BCNU used as standards. Its in vivo anti-tumoral potency was assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in these tumors. The survival time of treated mice was markedly increased by combination of the compound 1 with dopamine hydrochloride. Its toxicity was assessed in vivo in normal and EAC bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 30 mg/kg from day 1 to 7. Results indicated that initial suppression in the femoral bone marrow cellularity seen on day 9 reached normalcy by day 19. Other parameters were within normal limit. Histopathological studies of liver revealed mild hepatotoxicity on day 9 in treated groups that substantially recovered on day 19. Similar studies with heart and kidney revealed no cardio toxicity or nephrotoxicity. Compound 1 comparable to standards inhibited the synthesis of DNA and RNA in S-180 tumor cells.
Mukherjee
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Department of Anticancer Drug Development, Chittaranjan National Cancer Institute, Kolkata, India.
Dutta
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S
Sanyal
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U
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009607:Nitrosourea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014529:Uridine / Q000378:metabolism
C530564:1-(2-(3-(2-chloroethyl)-3-nitrosoureido)ethyl)-3,4-dimethoxy-benzene; D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D013936:Thymidine; D014529:Uridine