The radiobiology of intravascular irradiation

There is increasing interest in the use of vascular irradiation, from an internally introduced radioactive source to control restenosis after balloon angioplasty. Both animal experiments and early clinical studies appear to show promising results in this regard. We consider various mechanistic interpretations of the experimental and clinical observations that doses of 12-20 Gy appear to be efficacious in preventing restenosis. We develop and investigate simple models, both experimental and theoretical, of the kinetics of radiation-induced smooth muscle cell (SMC) inactivation and regrowth, as a first step toward optimizing the design of clinical vascular irradiation.

Using in vitro models of human SMCs, we investigate the relative radiosensitivity of SMCs compared with endothelial cells and measure the dose-dependent ability of SMCs to repopulate a denuded region in a confluent layer of cells. We then use quantitative information on the number, radiation sensitivity, and growth rate of the potential arterial target cells to model the time course of the SMC population after irradiation.

Doses >20 Gy, which would be required to completely eliminate the SMC population which has the potential to cause restenosis, are too large to be practical because of the unacceptable risk of late complications. However, doses that can be practically given in vascular irradiation (<20 Gy) will certainly delay restenosis by 1-3 years, with larger doses producing longer delays. Whether such doses can avert restenosis permanently is unclear, as permanent prevention at realistic doses depends critically on the assumption that those SMCs which survive irradiation have a significantly limited capacity for proliferation. With regard to current animal model experiments, routine follow-up of <1 year, which is standard practice, is probably too short to address some of the key mechanistic question in intravascular radiation therapy.