Radiosurgery of isolated cerebral vessels following administration of paclitaxel in the rat

Abstract

Progressive obliteration occurs in arteriovenous malformations (AVMs) after radiosurgery; however, the risk of hemorrhage remains until the obliteration process is complete. The authors sought to enhance the radiation effect and reduce the risk of hemorrhage by facilitating faster vessel obliteration. To that end, a combination of a lower radiation dose with the addition of a radiosensitizing agent was compared with the effect of a higher radiation dose alone. Using a method described by Mulvany and Halpern, isometric myography measurements were made on isolated rat middle cerebral artery specimens. The vessels were treated with 200 Gy, 80 Gy, 50 Gy, 25 Gy, 20 Gy, or 15 Gy by using Gamma Knife surgery. Taxol (paclitaxel 3 mg/kg/body weight) was administered intravenously to the animals. Survival times posttreatment were 24 hours, 6 weeks, 12 weeks, 12 months, or 18 months. After dissection, the middle cerebral arteries were mounted on a small-vessel myograph, and contraction and relaxation studies were performed. In a second series of experiments these results were validated in human fibroblast culture. When the cultures were 75 to 80% colonized, the samples were treated in vitro with 60Co gamma radiation in similar doses with or without paclitaxel. Constriction responses were generally decreased in the paclitaxel-treated vessels. Differences were significant at 6 weeks (p < 0.05) and at 1 year (p < 0.05). After 1 year, in the paclitaxel-treated groups vascular reactivity was completely abolished in vessels receiving 50 Gy. In comparison, it took 6 months longer (18 months) for this reaction to be abolished in vessels without paclitaxel treatment. In tissue cultures Giemsa staining and immunohistochemical reactions for p53, Ki-67, CD-34, and SMA antigens revealed marked fibroblast hypertrophy in all of the paclitaxel-treated groups. Paclitaxel-treated vessels demonstrated decreased reactivity at significantly earlier stages than vessels that had not been treated. It would appear that paclitaxel causes acceleration in the time course of the late biological effect of gamma radiation. This beneficial effect could be used in Gamma Knife surgery in patients with AVMs, thus reducing the risk of posttreatment hemorrhage.