Quantitative and qualitative effects of experimental radioimmunotherapy on tumor vascular permeability

Localization of radiolabeled antibodies in the perivascular space of tumors resulted in morphological changes in blood vessel structure and physiological changes in tumor vessel function. Vessel diameter decreased by day 14 and was associated with a significant decline in vascular volume (VV). Upon recovery of VV, the basement membrane surrounding the endothelium had thickened. Tumor vascular permeability (VP) decreased within 7 days of treatment and remained suppressed throughout the 42-day observation period of our study. The decline in VP, which could be visualized by fluorescent microscopy of FITC-dextran extravasation, was dose-related and could be quantified at doses as low as 800 cGy. The radioantibody-induced 50-80% decline in tumor VP was observed in 3 human colonic xenografts (GW-39, LSI74T and MOSER). Decreases in VP have been observed for proteins ranging in size from 20 to 150 kDa. Similar effects on VP were noted when low protein doses (10-30 micrograms), which resulted in heterogeneous antibody distribution, were used or with high protein doses (400-750 micrograms), which resulted in more uniform penetration of antibody. If 188Re or 90Y, radiometals with higher beta-energy and longer path lengths, were substituted for 131I, a similar decrease in VP was observed. The radioimmunotherapy (RAIT)-induced decrease in tumor VP resulted in a 90% decline in accretion of a second dose of radioantibody. The 10% of the second dose that was taken up by the tumor targeted many already non-viable tumor regions and some, but not all, viable tumor cell clusters.