The antiangiogenic agent ZD4190 prevents tumour outgrowth in a model of minimal residual carcinoma in deep tissues

Abstract

Background: Tumour cells may persist at the operative site after seemingly adequate surgery. Radiotherapy is often given in an attempt to prevent repopulation, but this modality cannot be relied upon to prevent locoregional recurrence. An alternative strategy is to take advantage of the requirement of tumour cells to develop an independent blood supply and block this process to prevent recurrence. Methods: In this study, we evaluate the effect of the angiogenesis inhibitor, ZD4190, using a rodent model of residual carcinoma in deep tissues, mimicking the clinical scenario where low numbers of malignant cells persist at the operative site. Results: The tumour burden that could be eliminated was dependent on the site where the cells were implanted. Immediate treatment with ZD4190 prevented outgrowth of up to 2.5 × 10 5 cells in the rectus muscle and 1 × 10 5 in the gastrocnemius, whereas control animals developed large tumours. When more than 2.5 × 10 6 cells were implanted into the rectus or 1 × 10 6 into the gastrocnemius and treatment was maintained for 3 weeks, the carcinomas that developed in ZD4190-treated animals showed a reduced microvessel density and increased necrosis when compared with the vehicle-treated controls, but an infiltrative growth pattern was common. Conclusion: These findings suggest that antiangiogenic agents have a role to play in preventing outgrowth of residual carcinoma and are likely to be most effective when the tumour burden is minimal.