Combretastatin A4 prodrug study of effect on the growth and the microvasculature of colorectal liver metastases in a murine model.

Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.