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In radioimmunotherapy (RIT), hematologic toxicity is the dose-limiting toxicity due to the long circulatory half-life of the antibody. Although intraperitoneal (i.p.) RIT results in high uptake of i.p. growing tumors, the radiolabeled antibody enters the circulation, resulting in bone marrow toxicity. Carbohydrate modification of antibodies could induce accelerated clearance of the antibody via the hepatic asialoglycoprotein receptor, thereby reducing exposure to normal tissues. In this study, we investigated whether galactosylation of an antibody in a model of peritoneal carcinomatosis (PC) of colonic origin could be used to improve targeting of i.p. growing tumors. Therefore, the biodistribution of the galactosylated and nongalactosylated anti-CC531 antibody, MG1, after i.p. injection was determined in a model of peritoneal carcinomatosis of CC-531 colon tumors in WagRij rats. Uptake of the radiolabeled antibodies in the tumor and relevant organs was determined at 2, 4, 24, and 48 hours after injection. Galactosylation of the antibody did not affect the binding affinity of MG1. Remarkably, the uptake of Gal-MG1 in tumors was higher than that of MG1 at 2 and 4 hours after injection. After 24 and 48 hours, uptake of Gal-MG1 in tumor tissue was lower than that of MG1. Gal-MG1 cleared from the blood within hours after administration. At 2–24 hours after administration, tumor-to-blood ratios obtained with Gal-MG1 were significantly higher than those obtained with unmodified MG1. Antibody galactosylation resulted in improved tumor-non-tumor ratios after i.p. injection in a model of PC. This could improve the efficiency of RIT, especially in combination with short-lived nonresidualizing radionuclides. [ABSTRACT FROM AUTHOR]

Background and ObjectiveCytoreductive surgery (CS) and heated intraperitoneal chemotherapy (HIPEC) are standard treatment for peritoneal carcinomatosis (PC) of colorectal cancer. Previously, we demonstrated that preclinical radioimmunotherapy (RIT) adjuvant to surgery in PC is a good alternative for HIPEC. Now we aimed to improve the effectiveness of RIT by combining it with whole-body hyperthermia (WBH) or fibrinolytic therapy. MethodsRats were inoculated intraperitoneally with colon carcinoma cells. Animals underwent CS, CS WBH (40°C, 3 hours), CS RIT (74 MBq 177Lu-labeled MG1), or CS WBH RIT. In the second experiment, rats underwent CS, CS RIT, CS recombinant tissue plasminogen activator (rtPA, twice daily, 3 days), or CS RIT rtPA. ResultsMedian survival after CS and CS WBH was 34 and 37 days. Median survival after CS RIT or CS RIT WBH was 63 and 86 days (p < 0.0003, p < 0.0006 compared to CS WBH). Median survival after CS and CS rtPA was 50 and 42 days (p 0.1). Median survival was 106 days after CS RIT and 103 days after CS RIT rtPA (p < 0.0001 compared to CS rtPA). No difference was found between CS RIT and CS RIT rtPA (p 0.83). ConclusionsThe application of WBH or rtPA in combination with adjuvant RIT after CS for the treatment of PC of colonic was feasible but did not significantly potentiate the efficacy of RIT. [ABSTRACT FROM AUTHOR]