Abstract 4180: A Single Cytostatic Dose of Mitomycin C Produces Sustained Smooth Muscle Cell Proliferation in vitro and Decreases Restenosis in the Atherosclerotic Rabbit Model
Background: We have demonstrated that local adventitial application of Mitomycin C (MMC) on a delivery gel inhibits neointimal proliferation in a rat model of balloon angioplasty. However, it is unknown if a single cytostatic dose of MMC is capable of maintaining an inhibitory effect over time or whether this “single-dose” effect could inhibit restenosis in vivo.
Methods: SMC were cultured in 24 wells at a density of 2.5×104 cells/well. A single dose of different concentrations of MMC (1 nM, n=6; 30 nM, n=6; and 100 nM, n=6) were administered and cell proliferation assessed after 7 (n=12) and 14 (n=12) days of initial exposure. 3 wells per time point were untreated as controls (n=6). In addition, the atherosclerotic rabbit model was used in the in vivo experiments. A total of 30 arterial iliac segments were balloon injured and randomized to adventitial delivery of a single-dose MMC using an endovascular micro-needle catheter (n=11), saline injection (n=15) or balloon injury only (n=4). Vessels were excised for histomorphometric analysis 8 days following randomization.
Results: The inhibitory effect of MMC was dose-dependent (7 days=1nm: 10%, 30nm: 33%, 100nm: 56% of cell inhibition, p >0.01) and was maintained up to 14 days (1nm: 14%, 30nm: 38%, 100nm: 67% of cell inhibition, p >0.01). The in vivo experiments showed that in the MMC there was a significant decrease in the mean percentage area of stenosis (17.2±3.8%) compared to either control saline (33.7±2.4%) or balloon injury group (43.3±3.2%; p<0.001). The control saline group showed increased proliferation in the muscular medial layer compared to MMC group (Saline injection 2.3±2.3mm2 vs. MMC injection 0.67±0.2 mm2, p<0.001).
Conclusion: The administration of a single dose of MMC inhibits SMC proliferation in a dose-dependent fashion and this inhibitory effect is sustained up to 14 days in vitro. In the atherosclerotic rabbit model, the adventitial delivery of a single cytostatic dose of MMc was capable of inhibiting restenosis following balloon injury. Due to the fact that this drug maintains its antiproliferative effect over time without the need of a carrier, MMc represents an alternative therapeutic agent to decrease restenosis following balloon angioplasty.