Inhibition of angiogenesis, tumour growth and metastasis by the NO-releasing vasodilators, isosorbide mononitrate and dinitrate.
1. The effect of the nitric oxide (NO)-producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice. 2. Isosorbide 5-mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose-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 which generates NO non-enzymatically. 3. Mice, implanted intramuscularly with 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 reduction 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. Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial 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 tumor growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.
Department of Pharmacology, Medical School, University of Patras, Greece.
E
E
Pipili-Synetos
A
A
Papageorgiou
E
E
Sakkoula
G
G
Sotiropoulou
T
T
Fotsis
G
G
Karakiulakis
M E
ME
Maragoudakis
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy*; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology*
D014665:Vasodilator Agents; D009569:Nitric Oxide; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate