A synthetic, nitrogenated antimetastatic and anti-angiogenic compound withlow toxicity in vivo

The design of more effective therapies for metastatic disease involves deve lopment of new compounds able to specifically block the malignant process. We demonstrated previously that a new synthetic nitrogenated compound 3'-1- chloroethyl-2,3-dihydro-1H-imidazo-(2,1-i)-purine-4-ium-7-yl-3'-deoxy-1',5' ,6'-tri-O-(methylsulfonyl)-muco-inositol chloride (DIC) had an anti-prolife rative activity on tumor cells in vitro. In the present work we demonstrate that DIC induces apoptosis on the LM3 murine mammary adenocarcinoma cell l ine in vitro and has anti-angiogenic activity in vivo. We also evaluated to xicity, biodistribution and anti-neoplastic properties of DIC in vivo. Toxi city studies allowed us to establish the LD50 (750 mg/kg body weight). Admi nistration of 250 mg/kg/day (LD10) for 6 days did not cause overt toxic eff ects. Biodistribution assays revealed that DIC was rapidly eliminated (60% at t=10 min), although it accumulated in tumor tissue at higher concentrati ons than in other tissues. Daily s.c. treatment with DIC (LD10) for 24 days significantly reduced the number of spontaneous lung metastases. These res ults suggest that DIC has the ability of impairing the metastatic developme nt by inhibiting angiogenesis and inducing apoptosis on tumor cells.