Antiproliferative profile of sirolimus and mycophenolate mofetil: impact of the SI/MPL ratio

BACKGROUND: Recently, preliminary data of the ORBIT study have been presented; coronary restenosis after oral treatment with sirolimus (SRL) was merely 7.7%. The present study thought to investigate the antiproliferative profile of SRL and mycophenolate mofetil (MMF), both as individual compounds and as a combined therapy. METHODS AND RESULTS: Proliferation studies were carried out with smooth muscle cells of human coronary arteries (human coronary smooth muscle cells, HCMSMC). SRL (0.01-1000 ng/ml) and MMF (0.005-500 microg/ml) were added in six descending concentrations, cell proliferation was studied at day 5. To characterize the clinical relevance of the data, the authors calculated a SI/MPL ratio between a significant antiproliferative effect (SI) in vitro and the maximal systemic plasma level (MPL) in vivo. The SI/MPL ratios of SRL and MMF were 0.16 and 0.014, respectively. Second, SRL (1 and 0.1 ng/ml) was combined with four concentrations of MMF (0.5 and 0.05 microg/ml) and MMF was combined with four concentrations of SRL. Additive and overadditive antiproliferative effects were found, no destruction of alpha-tubulin was detected. CONCLUSIONS: Thus, SRL and MMF exhibit dose-dependent direct antiproliferative effects with SI/MPL ratios smaller than one. Both agents, as individual compounds or as combined therapy, are candidates for an oral therapy of human coronary restenosis.