Anti-Tumoral and Toxicological Studies with 2-[4-{3-(2-Chloroethyl)-3-Nitrosoureido}butyl]-Naphthalimide, a Novel Nitrosourea Molecule

Abstract

AIM: In the present study, a novel nitrosourea compound was prepared. Its antitumor efficacy was evaluated on human tumor cell lines in vitro and murine tumors in vivo. Drug-induced toxicities in normal and tumor-bearing mice at its optimum dose and in human peripheral blood mononuclear cells were Investigated.METHODS: In vitro cytotoxicity was determined by MTT or SRB (sulphorhodamine B) colorimetric assay. In vivo activity was assessed by measuring the increase in the median survival time of drug-treated (T) over untreated control (C) mice. Drug-induced toxicities in respect of hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters and histopathology of liver and kidney were assessed in vivo in normal and sarcoma-180 bearing mice sequentially on days 9, 14 and 19 following drug treatment at 50 mg/kg dose at the schedule QD(subscript 1-7). Inhibition of DNA/RNA synthesis was measured by the incorporation of 3H-thymidine or 3Huridine uptake by Ehrlich ascites carcinoma (EAC) cells in vitro.RESULTS: Results indicated a significant cytotoxicity of 2-[4-{3-(2-chloroethyl)-3-nitrosoureido}butyl]-naphthalimide in histiocytic lymphoma U-937 cells in vitro and an excellent tumor regression effect in the mice with sarcoma-180 (T/C＞250) and EAC (T/C=217) tumors in vivo. No cardiotoxicity, hepatotoxicity or nephrotoxicity was reflected in biochemical parameters at the optimum dose. An initial hyposplenic cellularity and the femoral bone marrow suppression effect observed on day 9 reached normalcy by day 19. No adverse effect was observed on peripheral blood mononuclear cells. It inhibited the synthesis of DNA/RNA in EAC cells comparable to standards at the same concentration of 8 μM.CONCLUSION: Results warranted a promising therapeutic potential of 2-[4-{3-(2-chloroethyl)-3-nitrosoureido}butyl]-naphthalimide for further investigation.