Single and fractionated doses of radioimmunotherapy (RAIT) and standard chemotherapy (0.6 mg 5-FU/day and 0.36 leucovorin/day on days 1-5) result in decreases in vascular permeability (VP) in the GW-39 human colonic xenograft. The effect of a single dose of RAIT (MN-14 anticarcinoembryonic antigen, Mu-9 anticolon-specific antigen, PAM-4 anti-MUC-1, RS-7 and RS-11 antiepithelial glycoprotein labeled with 131I) has also been evaluated in 10 other tumors. Fourteen days after a fixed 1,500-cGy dose of RAIT, 3 colonic tumors (LS174T, HT-29 and MOSER) all exhibited decreases in VP (58, 75 and 70%, respectively). Two colonic (LoVo and GS-7) and 1 breast tumor (MDA-468) did not exhibit any change in VP, and 1 lung (CALU-3), 1 cervical (ME-180), 1 pancreatic (CaPan-1) and 1 breast cancer line (ZR-75) exhibited increases in tumor VP (214, 289, 170 and 139%, respectively). The differences in VP response to RAIT do not appear to be related to the type of tumor, the size of tumor or the antigen being targeted by RAIT. The differences in tumor VP response to RAIT are discussed in terms of the ability to achieve significant tumor accretion of a second dose of radioantibody on a multiple-dosing regimen. We have begun to investigate the mechanism(s) which regulate the varying responses of tumor VP to RAIT by assessing the role that nitric oxide plays. Administration of arginine, a substrate for nitric oxide synthase, results in increases in both baseline and RAIT-modified VP in GW-39 and ME-180 tumors.