Combination therapy using the cyclooxygenase-2 inhibitor Parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin

Abstract

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).

Conclusion: The COX-2 inhibitor Parecoxib does not enhance the therapeutic efficacy of RIT of experimental small volume peritoneal carcinomatosis of colonic origin.

Fig. 1

Anti-COX-2-immunohistochemical staining of a small, intraperitoneally growing LS174T xenograft, showing pronounced expression of the COX-2 enzyme (magnification = 200×)

Fig. 2

The PCI designated to mice with small intraperitoneal LS174T xenografts after treatment with either daily intraperitoneal administrations of saline or increasing dosages of Parecoxib (0.2 – 25.0 mg/kg) for 14 consecutive days. Lines indicate the median and range. There was a borderline significant trend towards a lower PCI at higher Parecoxib dosages (P=0.097)

Fig. 3

The tumor weight found in the mice with small intraperitoneal LS174T xenografts after treatment with either daily intraperitoneal administrations of saline or increasing dosages of Parecoxib (0.2 – 25.0 mg/kg) for 14 consecutive days. Lines indicate mean ± SD

Fig. 4

The uptake of ¹²⁵I-MN-14 in tumor expressed as percentage of the injected dose per gram (% ID/g), with of without daily intraperitoneal injections of Parecoxib (1.0 mg/kg or 5.0 mg/kg). Control mice received daily administrations of saline. Par Parecoxib

Fig. 5

Kaplan-Meier survival plot of mice with small intraperitoneal LS174T xenografts after intraperitoneal administration of ¹³¹I-MN-14 (125 μg/mouse), Parecoxib monotherapy (14 daily administrations at 1.0 mg/kg or 5.0 mg/kg), or RIT combined with Parecoxib. Par Parecoxib

Fig. 6

Scatter dot plot, specifying the tumor weight found at dissection. Lines indicate means ± SD. The variation between the groups is not statistically different (P=0.94). Par, Parecoxib