Combination therapy using the cyclooxygenase-2 inhibitor Parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin.
BACKGROUND
Inhibition of the COX-2 enzyme has been shown to have a radiosensitizing effect in epithelial cancers. The aim of this study was to investigate whether the efficacy of radioimmunotherapy (RIT) using 131I-labeled anti-CEA monoclonal antibody MN-14 could be enhanced by co-administration of the selective COX-2 inhibitor Parecoxib in mice with small volume (1-3 mm) peritoneal carcinomatosis of colonic origin.


METHODS
First, the efficacy of 14 daily injections of Parecoxib monotherapy (0-0.2-1.0-5.0-25.0 mg/kg) was determined in mice with intraperitoneal LS174T xenografts. Second, the influence of Parecoxib (1.0 or 5.0 mg/kg) on the biodistribution of 125I-MN-14 was assessed. Finally, the efficacy of RIT alone [125 microCi 131I-MN-14/mouse approximately 1/4 of the maximal tolerated dose (MTD)] was compared with that of Parecoxib monotherapy and RIT combined with daily injections of Parecoxib (1.0 or 5.0 mg/kg).


RESULTS
Parecoxib had no measurable antitumor effect up to the highest dose level (25 mg/kg). Parecoxib had no effect on the uptake of 125I-MN-14 in the intraperitoneal tumor xenografts or on normal tissue distribution. Median survival of the control mice and the mice treated with Parecoxib monotherapy (1.0 or 5.0 mg/kg) was 48.5 days, 52 days and 52 days (P=0.47). RIT alone significantly delayed the growth of the intraperitoneal xenografts resulting in a median survival of 87 days (P<0.0001). Mice treated with RIT + Parecoxib at 1.0 or 5.0 mg/kg had a median survival of 73.5 days and 76 days, respectively, which was not statistically different from survival after RIT alone (P=0.15).


CONCLUSIONS
The COX-2 inhibitor Parecoxib does not enhance the therapeutic efficacy of RIT of experimental small volume peritoneal carcinomatosis of colonic origin.
Koppe
Manuel J
MJ
Department of Surgery, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands.
Oyen
Wim J G
WJ
Bleichrodt
Robert P
RP
Hendriks
Thijs
T
Verhofstad
Albert A
AA
Goldenberg
David M
DM
Boerman
Otto C
OC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary*; D003110:Colonic Neoplasms / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary*; D016499:Radioimmunotherapy; D013534:Survival; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D016861:Cyclooxygenase Inhibitors; D007457:Iodine Radioisotopes; D007555:Isoxazoles; C409945:parecoxib