Intraperitoneal paclitaxel induces regression of peritoneal metastasis partly by destruction of peripheral microvessels

Abstract

Intraperitoneal (IP) administration of paclitaxel (PTX) can enable direct infiltrate of high amount of PTX into peritoneal nodules and elicit remarkable clinical responses against peritoneal metastases. In this study, we examined the mechanisms leading to tumor shrinkage after IP PTX. We compared the microscopic features of peritoneal metastases before and after IP PTX in surgically removed human samples, as well as in a murine xenograft model using immunohistochemistry. We found that many microvessels exist in the peripheral areas of metastatic nodules in human samples before treatment. However, peripheral vessels were greatly reduced in number, and luminal obstructions were observed in lesions showing complete response after chemotherapy including IP PTX. Similar changes were observed in peripheral vessels of peritoneal tumors in MKN45-inoculated nude mice treated with IP-PTX. Moreover, pimonidazole staining revealed that highly hypoxic regions were produced by IP PTX at the tumor periphery. These findings strongly suggest that the remarkable efficacy of IP PTX in the treatment of peritoneal metastases is, at least in part, dependent on the destruction of peripheral microvessels by exposure to infiltrated PTX.