CHANGES IN TUMOR VASCULAR-PERMEABILITY IN RESPONSE TO EXPERIMENTAL RADIOIMMUNOTHERAPY - A COMPARATIVE-STUDY OF 11 XENOGRAFTS

Single and fractionated doses of radioimmunotherapy (RAIT) and standar d chemotherapy (0.6 mg 5-FU/day and 0.36 leucovorin/day on days 1-5:I result in decreases in vascular permeability (VP) in the GW-39 human c olonic xenograft. The effect of a single dose of RAIT (MN-14 anticarci noembryonic antigen, Mu-9 anticolon-specific antigen, PAM-4 anti-MUC-1 , RS-7 and RS-11 antiepithelial glycoprotein labeled with I-131) has a lso been evaluated in 10 other tumors. Fourteen days after a fixed 1,5 00-cGy dose of RAIT, 3 colonic tumors (LS174T, HT-29 and MOSER) all ex hibited decreases in VP (58, 75 and 70%, respectively). Two colonic (L oVo 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 (21 4, 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 tu mor or the antigen being targeted by RAIT. The differences in tumor VP response to RAIT are discussed in terms of the ability to achieve sig nificant tumor accretion of a second dose of radioantibody on a multip le-dosing regimen. We have begun to investigate the mechanism(s) which regulate the varying responses of tumor VP to RAIT by assessing the r ole that nitric oxide plays. Administration of arginine, a substrate f or nitric oxide synthase, results in increases in both baseline and RA IT-modified VP in GW-39 and ME180 tumors.