INHIBITION OF ANGIOGENESIS, TUMOR-GROWTH AND METASTASIS BY THE NO-RELEASING VASODILATORS, ISOSORBIDE MONONITRATE AND DINITRATE

1 The effect of the nitric oxide (NO)-producing nitrovasodilators isos orbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assesse d on (a) the in vivo model of angiogenesis of the chick chorioallantoi c membrane (CAM) and (b) on the growth and metastatic properties of th e Lewis Lung carcinoma (LLC) in mice. 2 Isosorbide 5-mononitrate (ISMN ) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM d ose-dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of alpha-thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside whi ch generates NO non-enzymatically. 3 Mice, implanted intramuscularly w ith LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a redu ction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN.4 A ddition of ISMN or ISDN to cultures of bovine, rabbit and human endoth elial cells and to cultures of LLC cells had no effect on their growth characteristics. 5 These results indicate that ISMN and ISDN inhibit angiogenesis and tumour growth and metastasis in an animal tumour mode l. The possibility should therefore be considered that these nitrovaso dilators which are widely used therapeutically and have well character ized pharmacological profiles, may also possess antitumour properties in the clinic.