In this study the efficacy of treatment of two
cyclo-oxygenase inhibitors,
ibuprofen (Ibu) and
indomethacin (Indo), are compared in the
immunotherapy of
metastasis designed to reverse
prostaglandin E2 (PGE2)-mediated inactivation of
interleukin-2 (IL-2)-dependent host killer cell lineages. These agents were tested either alone for the prevention of
metastasis or in combination with
IL-2 for the eradication of established
metastasis. C3H/HeN mice were placed on chronic oral Ibu (CIbT; 200 and 600 micrograms/ml of water) or Indo (
CIT; 10 micrograms/ml) 5 days after s.c.
transplantation of 5 x 10(5) metastatic C3L5 mammary
carcinoma for the prevention of spontaneous lung
metastases. They showed intolerance to Indo at a dosage of 14 micrograms/ml, which was well tolerated by other mouse strains in previous studies, but tolerated the Ibu dosages used. Control and treated mice were killed on day 30 to score metastatic lung colonies, to evaluate killer activity in splenocytes against natural killer (NK)-sensitive YAC-1
lymphoma or NK-resistant C3L5
adenocarcinoma and 8911
lymphoma targets, and to phenotype the surface markers of killer cells. CIbT and
CIT alone at the above dosage significantly reduced the number of lung colonies, retarded local
tumor growth and restored NK activity of splenic killer cells expressing AGM-1+, Thy-1-, Lyt-2- phenotype. To treat established lung
metastasis, mice bearing 15-day C3L5 transplants were given CIbT or
CIT alone or in combination with two 4-day rounds (days 20-23, 31-34) of
IL-2 (15,000 Cetus units, i.p. every 8 h) and were killed on day 35 to score lung colonies and characterize splenic killer cells. CIbT or
CIT alone reduced the number of spontaneous lung
metastases and restored anti-YAC-1 killer function of splenocytes with NK-like phenotype (AGM-1+, Thy-1-, Lyt-2-); some anti-C3L5 killer function was also generated in the high dose Ibu group and the killer cell showed AGM-1+, Thy-1+ and Lyt-2+ phenotype. Combined
therapies with CIbT or
CIT plus
IL-2 were more effective in reducing
metastases and promoting killer cell function, the best results being achieved with high dose Ibu+IL-2. All killer cells expressed AGM-1 and Thy-1. In addition, C3L5 killer cells also expressed Lyt-2, suggesting T-cell stimulation.
PGE2 synthesis in the host was inhibited by at least 50% in mice subjected to CIbT or
CIT.(ABSTRACT TRUNCATED AT 400 WORDS)